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CONGRESO

INTERNACIONAL

DE MEDICINA

Y CIRUGÍA

EQUINA

sicab’13

6 Y 7 DICIEMBRE 2013. sevilla

Y CIRUGÍA EQUINA sicab’13 6 Y 7 DICIEMBRE 2013. sevilla Europa invierte en las zonas rurales
Y CIRUGÍA EQUINA sicab’13 6 Y 7 DICIEMBRE 2013. sevilla Europa invierte en las zonas rurales
Europa invierte en las zonas rurales
Europa
invierte en las zonas rurales
6 Y 7 DICIEMBRE 2013. sevilla Europa invierte en las zonas rurales Consejería de Agricultura, Pesca

Consejería de Agricultura, Pesca y Desarrollo Rural

XIV Congreso Internacional de Medicina y Cirugía Equina

XIV Congreso Internacional de Medicina y Cirugía Equina Consejería de Agricultura, Pesca y Desarrollo Rural
XIV Congreso Internacional de Medicina y Cirugía Equina Consejería de Agricultura, Pesca y Desarrollo Rural

Consejería de Agricultura, Pesca y Desarrollo Rural

Congreso Internacional de Medicina y Cirugía Equina (14. 2013. Sevilla) 14º Congreso Internacional de Medicina y Cirugía Equina : SICAB´13, Sevilla, 6 y 7 de diciembre de 2013.-- Sevilla : Consejería de Agricultura, Pesca y Desarrollo Rural, 2013. 390 p. : il. ; 24 cm.-- (Ganadería (congresos y jornadas))

Datos tomados de la cub. D.L. SE 2376-2013 Ganadería. -- Equinos. -- Sanidad animal. -- Congresos y asambleas

636.1.09(063)

614.9(063)

XIV CONGRESO INTERNACIONAL DE MEDICINA Y CIRUGÍA EQUINA

© Edita: JUNTA DE ANDALUCÍA. Consejería de Agricultura, Pesca y Desarrollo Rural

Publica: Secretaría General Técnica. Servicio de Publicaciones y Divulgación

© Textos: Autores

© Ilustraciones: Autores

Colección: Congresos y Jornadas

Serie: Ganadería

Depósito Legal: SE-2376-2013

Maquetación e Impresión: LUMEN GRÁFICA, S.L. (Sevilla)

XIV Congreso Internacional de Medicina y Cirugía Equina SICAB´13 Sevilla 6 y 7 de diciembre

XIV Congreso Internacional de Medicina y Cirugía Equina

SICAB´13

Sevilla

6 y 7 de diciembre de 2013

Palacio de Exposiciones y Congresos FIBES

ORGANIZA:

Organización Colegial Veterinaria Asociación Andaluza de Veterinarios Especialistas en Equidos

www.congresoequino.com

Índice

PONENCIAS

9

Laminitis – an endocrine or inflammatory disease?

11

How to understand and recognise laminitis of endocrine origin

19

Useful laboratory tests in horses predisposed to laminitis

43

Dietary control of obesity and laminitis risk

65

Treatment and monitoring of horses with Pituitary Pars Intermedia Dysfunction

71

Pharmacologic treatment of the Equine Metabolic Syndrome

79

What Is Laminitis For A Podiatrist?

87

The use of venogram as a prognostic, diagnostic tool and to monitor response to treatment

95

The equine foot pump theory in dynamic, in quasi-static and static, state of arts

107

Endocrinopathic equine laminitis a podiatry vet-ferrier perspective

113

Instrumental therapy, brand new and old thecnologies in the management of laminitis

123

New instrumental therapy thecnologies have radically changed my therapeuticl approach for high risk laminitis cases candidate for aggressive surgery

135

COMUNICACIONES

141

Relación entre la aldosteronemia y diversos parámetros hidroelectrolíticos en yeguas pura raza española durante la fase luteal del ciclo estral

143

Inducción de la lactación en la yegua y adopción en el potro huérfano

147

Muerte súbita en caballos pura sangre inglés de carrera. Hipódromo “La Rinconada” Caracas-Venezuela

153

Estudio patológico de las causas de mortalidad en caballos pura sangre inglés de carrera en Venezuela periodo 2011

159

Estudio patológico de las causas de mortalidad en burros en Bodonal de la Sierra, Badajoz-España

165

Hemangiosarcoma cavernoso esplénico en un caballo de pura raza española. Estudio clínico patológico

169

165 Hemangiosarcoma cavernoso esplénico en un caballo de pura raza española. Estudio clínico patológico 169 5

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Estudio retrospectivo de cojeras en el caballo español; Prevalencia de lesiones y caracterÍsticas en 130 caballos

173

Cáncer de ranilla: A propósito de 2 casos clínicos

179

Odontoma. A propósito de un caso clínico

185

Análisis del patrón locomotor mediante acelerometría de caballos sedados con Acepromacina

191

Prevalencia y distribución de la osteocondrosis en caballos de pura raza española valorados en TRC fuera de españa

197

Caso clínico: Exóstosis en el aspecto palmar de la diáfisis del tercer metacarpiano

203

Diagnóstico de un quiste en el seno esfenopalatino mediante resonancia magnética

211

Acceso laparoscópico directo por el flanco derecho del caballo en estacion con cánula óptica helicoidal

215

Estudio retrospectivo de úlceras corneales complicadas en caballos: 17 casos (2011-2013) 219

Actividad de la enzima de conversión de la angiotensina (ECA) tras la administración de ramiprilo en el caballo

225

Pérdida de rendimiento en competición en un caballo de raid con eritrocitosis absoluta

231

Uso de insulina glargina en el tratamiento de hiperglucemia transitoria neonatal en un American Miniature

237

Comparación entre dos técnicas de inyección de la bursa podotroclear

243

Estimación de obesidad en caballos pre como factor de riesgo de laminitis

247

Exposición a parásitos hepáticos en caballos en pastoreo

251

Aplicación de curvas ROC al diagnóstico clínico de estrongilosis parasitarias en caballos

257

¿Cómo tratar de urgencia a los caballos con micosis de bolsas guturales? 3 casos

265

Radiología de la osteoartritis intervertebral toracolumbar del caballo: estudio retrospectivo

273

Resolución del desplazamiento dorsal izquierdo de colon mayor y cierre del espacio nefroesplénico mediante laparoscopía en estación asistida manualmente

277

Laminitis con rotación medial de la tercera falange bilateral de las extremidades anteriores

283

Quiste sinusal multilobulado en seno maxilar rostral y caudal en un caballo

289

Pronóstico deportivo en caballos con fragmentos en el proceso extensor de la tercera falange extraídos mediante cirugía artroscópica. 10 Casos Clínicos

295

Épuli fibromatoso de origen periodontal con infiltración dentaria en un caballo

301

10 Casos Clínicos 295 Épuli fibromatoso de origen periodontal con infiltración dentaria en un caballo 301

6

Índice

Valores de ACTH basal y respuesta al test de estimulación con TRH en caballos PRE

307

Atresia Coli en un potro neonato

313

Meningoencefalitis verminosa: tres casos clínicos

321

Cólicos por lesiones de colon menor: 17 casos

323

Ostectomía parcial del Sustentaculum Tali

329

Ultrasonografía doppler en la arterial digital palmar en caballos con laminitis

335

Fractura del proceso odontoides de la segunda vértebra cervical en un caballo adulto

341

Valoración de la técnica de monta natural de sementales mediante el uso del colector cervical y subsiguiente corrección de patologías posturales

347

Intoxicación por adelfas en equidos

351

Aislamiento y caracterización de Células madre mesenquimales del corion coronario del casco equino

355

Evaluación del efecto, las condiciones de uso y el coste de un dispositivo artesanal para la crioterapia preventiva de la extremidad distal del caballo

359

Miopatía de los músculos rectos dorsales mayor y menor en un caballo

363

Desarrollo de una aplicación informática para aprender clínica y producción equina jugando al trivial

371

Disfagia como posible complicación de la laringoplastia

373

Respuesta del Folículo Preovulatorio de la Yegua a la Administración de un Protocolo de 5 días con Altrenogest

379

Estudio radiográfico de la región de la cruz del caballo: 29 casos

383

de 5 días con Altrenogest 379 Estudio radiográfico de la región de la cruz del caballo:

7

PONENCIAS

LAMINItIS – AN ENDOCrINE Or INfLAMMAtOry DISEASE?

Andy Durham BSc.BVSc.CertEP.DEIM.DipECEIM.MRCVS.

Liphook Equine Hospital, Portsmouth Road, Liphook, GU30 7JG. 01428 727200. andy.durham@theleh.co.uk

Understanding the causes and epidemiology of laminitis is very important to enable preventive measures to be put in place to avoid recurrence of disease. If the causal factors of laminitis are not identified and controlled then clearly it is inevitable that recurrences will happen most likely leading eventually to structural damage to the foot which may become irreversible.

Causation of laminitis in a clinical and experimental setting can essentially be divided into 3 categories: inflammatory, endocrinopathic and excess weight bearing. This latter category, although well recognised, is not frequently encountered and has had little research-based attention. It is well recognised clinically that if horses bear excessive weight on one limb without rest or relief then laminitis may follow presumably via ischaemic and hypoxaemic mechanisms. This is generally seen when horses choose to bear weight unevenly due to a fracture or severely painful condition affecting the contralateral limb. Thus, from a general aetiologic perspective the 2 main subcategories of laminitis comprise inflammatory and endocrinopathic mechanisms.

INfLAMMAtOry LAMINItIS

Various disease processes associated with a systemic inflammatory response seen in clinical practice are known to carry a risk of laminitis. These include problems such as retained foetal membranes, intestinal strangulations (e.g. colon torsion), pleuropneumonia and colitis (e.g. infectious colitis or feeding accidents (grain overload)). A similar disease process can be mimicked and reproduced experimentally by enteral dosing of horses with 5-10 g/kg BWT starch or oligofructose. The model requires loading with more carbohydrate than can be hydrolysed and absorbed by the upper gastrointestinal (GI) tract which then results in arrival of significant quantities of rapidly hydrolysable carbohydrate in the caecum

(GI) tract which then results in arrival of significant quantities of rapidly hydrolysable carbohydrate in the

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and colon (mimicking feeding accidents). Acidosis, dysbacteriosis, typhlocolitis and mucosal barrier compromise follow which facilitates absorption of unknown toxins and “trigger factors” into the plasma which subsequently result in laminitis. This type of laminitis is associated with a severe local and systemic inflammatory response and is clearly an “inflammatory laminitis”. Additionally it has been found that enteral dosing of black walnut shavings also predictably results in laminitis. Again, the precise causal toxin is not known although this form of laminitis is associated with a significant inflammatory process also.

ENDOCrINOPAthIC LAMINItIS

Laminitis is a key component and consequence of equine metabolic syndrome (EMS) and pituitary pars intermedia dysfunction (PPID) which are collectively the commonest clinical endocrinopathies of horses. Laminitis also occurs predictably following exogenous insulin administration and also, less predictably, following exogenous glucocorticoid administration. Collectively these conditions represent endocrinopathic laminitis and this appears to develop in the absence of a notable systemic inflammatory response.

Two separate studies from different continents both found that approximately 90% of laminitis cases showed evidence of an underlying endocrinopathy (Donaldson et al 2005; Karikoski et al 2012). Although perhaps initially surprising, such a high prevalence of endocrinopathic laminitis is entirely consistent with general clinical experience and observation where the vast majority of laminitis cases seen in general equine practice occur in readily identifiable, “at risk” individuals typified by the defining characteristics of EMS and/or PPID including breed, age, obesity, activity and dietary excess. There are essentially 2 types of laminitis! Type 1 can be seen in any individual of any breed or type or age or activity – whether this is a fat native pony or a young, lean and fit Thoroughbred. Examples include problems such as feeding accidents, retained foetal membranes, colitis, etc… (i.e. inflammatory causes) and represent the minority (<10%) of cases seen in general practice (NB. may be more common in racing practice). Type 2 is laminitis that is seen almost exclusively in certain identifiable and susceptible individuals (e.g. overweight, inactive, overfed, particular breeds or PPID phenotype and NOT in a lean, fit Thoroughbred or Standardbred) and is frequently associated with grazing. This is clearly the predominant form of laminitis seen in general practice (>90% of cases) and supports the estimates of high prevalence of endocrinopathic forms of the disease in the studies mentioned above.

In considering the pathophysiology of laminitis in endocrinopathic cases, our focus has been drawn to the commonly shared feature of insulin resistance (IR) in such individuals. However, IR tends to be associated with the further components of hyperinsulinaemia and hyperglycaemia which might also be of pathogenic importance (Fig 1). Secondary hyperinsulinaemia could result from a compensatory pancreatic response in the face of primary IR and/or possible reduced rates of clearance of insulin from plasma (Toth et al 2012). Conversely (or additionally), it may be that the causal relationship is reversed and

from plasma (Toth et al 2012). Conversely (or additionally), it may be that the causal relationship

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Laminitis – an endocrine or inflammatory disease?

that a primary tendency towards hyperinsulinaemia may promote secondary tissue IR. This might simply be from down-regulation of insulin receptors in the face of high circulating plasma insulin concentrations. Alternatively it may be that a primary inherent (genetically determined) tendency towards hyperinsulinaemia in certain individuals promotes obesity via the known anabolic effects of insulin on adipose tissue, and this developing obesity then leads to secondary tissue IR. The 3 rd related component of hyperglycaemia may result from glucose intolerance as tissue insulin insensitivity fails to promote normal tissue uptake of glucose from plasma into insulin-sensitive tissues. Should hyperglycaemia develop then this will tend to further stimulate secondary hyperinsulinaemia. Thus, the 3 components of tissue IR, hyperinsulinaemia and hyperglycaemia are closely inter-related, but are not synonymous or even always coexistent.

The concept of a primary tendency towards either IR or hyperinsulinaemia makes sense in evolutionary terms. Many breeds known to be prone to laminitis evolved in nutritionally sparse environments where food supply may have been both poor and inconsistently available. Evolutionary development of relative resistance to the effects of insulin would have the metabolic advantages of prioritisation and preservation of glucose for non- insulin dependent tissues such as the brain, kidneys, heart and laminae, and additionally the capacity to more rapidly mobilise glycogen and adipose stores when feed becomes unavailable (eg. during drought or snow). Evolutionary development of a tendency towards hyperinsulinaemia is also logical. In harsh environments ingestion of significant amounts of nutrients that stimulate insulin secretion such as glucose would be a relatively rare event. Under such circumstances individuals may have developed a relatively decreased beta-cell threshold for glucose-induced insulin secretion (otherwise insulin would never be secreted!) which then becomes overstimulated resulting in excessive hyperinsulinaemia when exposed to diets typical of modern domesticated horses and ponies.

to diets typical of modern domesticated horses and ponies. Figure 1. Schematic demonstrating the possible

Figure 1. Schematic demonstrating the possible interrelationships of insulin resistance, hyperinsulinaemia and hyperglycaemia.

Schematic demonstrating the possible interrelationships of insulin resistance, hyperinsulinaemia and hyperglycaemia. 13

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Probably the most straightforward putative mechanism whereby endocrinopathic laminitis might arise would be via decreased laminar uptake of glucose associated with tissue IR. It is known that the laminae have an exceptional requirement for glucose (Wattle and Pollitt 2004) and, should insulin fail to promote normal cellular uptake of glucose then laminar failure might follow (Pass et al 1998). However this theoretical explanation appears unlikely given that laminar epithelial cells have been found not to express GLUT4, the main insulin-dependent glucose transporter. Rather, these cells are found to express GLUT1 which represents a transporter whereby plasma glucose is taken into laminar cells without the involvement or requirement for insulin.

In humans with metabolic syndrome, hyperglycaemia is considered to be an important pathogenic factor. However, it is immediately doubtful that this is of importance in horses with EMS or PPID given that resting hyperglycaemia is uncommon (in contrast to humans). Additionally studies have failed to demonstrate markers of glucotoxicity such as advanced glycation end products (AGEs) during development of hyperinsulinaemic laminitis (de Laat et al 2012a).

Currently the only successful experimental model of endocrinopathic laminitis involves hyperinsulinaemia. Asplin et al (2007) first described that experimental maintenance of marked hyperinsulinaemia (> 1000 mU/mL) in the face of normoglycaemia in healthy, young, non-obese, non-IR ponies with no history of laminitis, using a modified hyperinsulinaemic euglycaemic clamp (HEC) consistently led to clinical laminitis within 48 hours suggesting that hyperinsulinaemia (“insulin toxicity”) was of primary importance in the development of laminitis. Subsequently de Laat et al (2010) found the same model to be similarly effective in triggering laminitis in insulin sensitive Standardbred horses. A further study by de Laat et al (2012b) attempted to investigate the possible relevance of hyperglycaemia by infusing glucose at the same rate as used in the HEC, but without exogenous insulin. This resulted in hyperglycaemia (10 mmol/L) and moderate endogenous hyperinsulinaemia (200 mU/L) and very mild laminitic changes detectable histopathologically, but not clinically. Collectively these studies suggested that hyperinsulinaemia was the primary mechanism for development of laminitis and that hyperglycaemia, if relevant, was of more minor importance. As none of the horses and ponies in the above studies had IR, this also did not appear necessary for development of laminitis. Although hyperinsulinaemia appears to be the most likely trigger factor for endocrine laminitis, the pathogenetic relevance of IR and hyperglycaemia cannot be entirely discounted even if from indirect influences on promoting hyperinsulinaemia.

The putative mechanism by which hyperinsulinaemia might trigger laminitis is not fully understood although several possibilities exist. Although, as mentioned above, laminar epithelial cells are not responsive or dependent on insulin, this is not the case for digital blood vessels which do possess insulin receptors and responsiveness to insulin. Insulin is a vasoactive hormone which may provoke either nitric oxide mediated vasodilation or endothelin-mediated vasoconstriction through differing intracellular pathways (PI3 kinase and MAP kinase pathways respectively). It is hypothesised that IR causes preferential

pathways (PI3 kinase and MAP kinase pathways respectively). It is hypothesised that IR causes preferential 14

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Laminitis – an endocrine or inflammatory disease?

impairment of PI3 kinase pathways allowing the vasoconstrictive MAP kinase/endothelin pathway to predominate and perhaps be additionally stimulated when hyperinsulinaemia is also present. Equine studies have demonstrated that vascular ring preparations exposed to insulin for as little as 30 minutes became vasoconstricted in response to further exposure to insulin, in marked contrast to the vasodilation occurring in control vessels without prior insulin exposure (Venugopal et al 2011).

Apart from possible vascular effects, insulin might also mediate dysregulation of cellular growth and differentiation. Hyperinsulinaemic laminitis is noted to be associated with apparent elongation of epidermal lamellae and also increased apoptosis and considerable mitotic activity of laminar epithelial cells. These changes in lamellar cellular activity may well be relevant to laminitis development and could be mediated via insulin like growth factor-1 receptors which, unlike insulin receptors, are indeed present on laminar epithelial cells.

It is possible that all forms of endocrinopathic laminitis share the same pathogenetic pathway in development of laminitis and a tendency towards excessive hyperinsulinaemia is a feature of phenotypic EMS cases, PPID and exogenous glucocorticoid administration. It is well recognised that certain identifiable individuals are more likely to develop laminitis than others and it is interesting to observe how this individual laminitis-predisposition corresponds to insulin dynamics. Several studies have indicated that hyperinsulinaemic responses to glucose feeding are very different in certain individuals. Ponies have been shown to demonstrate far greater hyperinsulinaemic responses to glucose ingestion than horses (Tinworth et al 2011), and, furthermore, laminitis-prone ponies demonstrate far higher insulinaemic responses to glucose, fructose or fructan ingestion than non-laminitic ponies (Bailey et al 2007; Borer et al 2012). Similar findings have been demonstrated in PPID cases also (Durham unpublished data). It is tempting to speculate that this inherent tendency towards an excessive insulinaemic response mimics events that occur following consumption of non-structural carbohydrate-rich pasture.

Thus it is hyperinsulinaemia, rather than IR, that is most deserving of our focus with respect to diagnostic testing for a laminitis predisposition and also for treatment and management procedures to target for control. Although hypercortisolaemia has been previously considered as a pathogenetic mechanism explaining laminitis in PPID cases, this may well have arisen following confusion and lack of distinction between PPID and analogous conditions in other species that result in pituitary-dependent hyperadrenocorticism. However, there is little if any evidence to support the coexistence of PPID with hyperadrenocorticism or hypercortisolaemia in horses. Adrenal hypertrophy is reported to be relatively rarely in PPID cases, most likely due to the observation that the increased measured plasma ACTH concentrations in PPID cases does not appear to possess normal bioactivity. Furthermore, plasma cortisol concentrations in PPID cases are indistinguishable from those of normal horses. In contrast to the lack of scientific support for hypercortisolaemia as a cause of laminitis in PPID, the evidence for involvement of hyperinsulinaemia is compelling. McGowan et al (2004) noted that more hyperinsulinaemic PPID cases were more likely to develop laminitis and were

McGowan et al (2004) noted that more hyperinsulinaemic PPID cases were more likely to develop laminitis

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XIV CONGRESO INTERNACIONAL DE MEDICINA Y CIRUGÍA EQUINA

less likely to survive than horses with lower plasma insulin concentrations. Additionally Walsh et al (2009) demonstrated an association between plasma insulin levels and grade of laminitis. Hence, it is plausible that hyperinsulinaemia is a common pathogenic pathway important in development of laminitis in both EMS and PPID cases. In EMS cases this hyperinsulinaemic response may derive from a genetic predisposition towards exaggerated pancreatic secretion possibly augmented by tissue IR resulting from obesity.

In PPID cases the hyperinsulinaemic response is less clearly explicable although the pars

intermedia is known to produce peptides known to be insulin secretagogues such as beta cell tropin and this might provide an explanation for the hyperinsulinaemia seen in non-obese PPID cases.

Pasture grazing (or excess cereal ingestion) is a very common event preceding numerous laminitis cases seen in practice and it is interesting to speculate just how consumption of grass might lead to laminitis and how this fits with our understanding of inflammatory and endocrinopathic laminitis. Pathogenetic focus has inevitably fallen on the non-structural carbohydrate (NSC) component (simple sugars, starches and fructans) within grass as the likely provocateur of laminitis although this is not known for sure. Nevertheless it is interesting to speculate how grass NSC might feasibly trigger laminitis. In the context of inflammatory laminitis it is might be argued that the large and indigestible fructan component of NSC in temperate grass species passes through the upper GI tract and arrives in the colon where bacterial hydrolysis results in acidosis and barrier dysfunction as is seen in carbohydrate overload models of laminitis. These latter studies have indicated that, in order to provoke laminitis,

a minimum enteral bolus dose of >5 g/kg BWT starch or oligofructose is required.

Alternatively it may be that ingestion of grass NSC (and/or perhaps proteins) leads to small intestinal assimilation of simple sugars (and/or aminoacids) which provoke insulin secretion and hyperinsulinaemic laminitis. Several studies (Bailey et al 2007, Tinworth et al 2011; Borer et al 2012) suggest that ingestion of <1 g/kg BWT NSC will provoke hyperinsulinaemia above the threshold known to be associated with laminitis development (de Laat et al 2010).

In the context of naturally occurring pasture-induced laminitis it is then interesting to

speculate how much NSC a grazing pony could feasibly consume and how this relates to the supposed pathogenic thresholds above. Considering even a fairly extreme example of grazing ponies eating up to 10 g dry matter (DM) per kg BWT in a 3 hour grazing period, and an extreme example of grass NSC content of 40% DM, it is apparent that an intake of more than 1-2 g NSC/kg BWT per hour is implausible; and far lower rates (<0.5 g NSC/kg BWT/hour) are more probable with realistic grazing activity. Whether the extreme or typical figures for intake are considered it is hard to conceive how this level of intake could cause barrier dysfunction similar to that seen when 5-10 g/kg starch or oligofructose are administered as a single bolus. In contrast, an hourly intake of 0.5 g/kg NSC could maintain a hyperinsulinaemia similar to models of hyperinsulinaemic laminitis. Thus grass most likely induces laminitis via endocrinopathic mechanisms and the observation that pasture is a common trigger for laminitis and the above consideration

mechanisms and the observation that pasture is a common trigger for laminitis and the above consideration

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Laminitis – an endocrine or inflammatory disease?

of pathogenically relevant rates of intake is additional support that the majority of cases of laminitis seen in horse and ponies are endocrinopathic in origin. Interestingly it would appear that a similarly excessive hyperinsulinaemic response may also be provoked by exogenous glucocorticoids (French et al 2000; Tiley et al 2008), again in certain predisposed individuals (Bailey et al 2007).

Thus laminitis may be either an endocrine or an inflammatory disease, or it may be neither and result from laminar ischaemia secondary to excessive weight bearing. However there is compelling evidence that laminitis is triggered most commonly by hyperinsulinaemia. Although mild hyperinsulinaemia inevitably results from pasture ingestion by any horse, it appears that certain individuals possess an inherent tendency towards excessive hyperinsulinaemia that may be above the threshold for development of hyperinsulinaemic laminitis. Such predisposition is generally represented by EMS or PPID. The important clinical implication of the recognition of the very high prevalence of endocrinopathic mechanism underlying laminitis in the horse is that, in the absence of obvious alternative explanations for laminitis (e.g. colitis, retained foetal membranes, excessive weight bearing) then it should be assumed that an endocrinopathic condition underlies all cases of laminitis and appropriate investigation, treatment and management should then follow.

rEfErENCES

1. Asplin KE, Sillence MN, Pollitt CC, McGowan CM. 2007 Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies. Vet J. 174: 530-5

2. Bailey SR, Menzies-Gow NJ, Harris PA, Habershon-Butcher JL, Crawford C, Berhane Y, Boston RC, Elliott J. 2007 Effect of dietary fructans and dexamethasone administration on the insulin response of ponies predisposed to laminitis. J Am Vet Med Assoc. 231: 1365-73Borer KE, Bailey SR, Menzies-Gow NJ, Harris PA, Elliott J. 2012 Effect of feeding glucose, fructose, and inulin on blood glucose and insulin concentrations in normal ponies and those predisposed to laminitis.J Anim Sci. 90(9):3003-11.

3. de Laat MA, McGowan CM, Sillence MN, Pollitt CC. 2010 Equine laminitis: induced by 48 h hyperinsulinaemia in Standardbred horses. Equine Vet J. 42: 129-35

4. de Laat MA, Kyaw-Tanner MT, Sillence MN, McGowan CM, Pollitt CC. 2012a Advanced glycation endproducts in horses with insulin-induced laminitis. Vet Immunol Immunopathol. 145(1-2):395-401.

5. de Laat MA, Sillence MN, McGowan CM, Pollitt CC. 2012b Continuous intravenous infusion of glucose induces endogenous hyperinsulinaemia and lamellar histopathology in Standardbred horses. Vet J. 191: 317-22

of glucose induces endogenous hyperinsulinaemia and lamellar histopathology in Standardbred horses. Vet J. 191: 317-22 17

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6. Donaldson MT, Jorgensen AJ, Beech J. 2004 Evaluation of suspected pituitary pars intermedia dysfunction in horses with laminitis. J Am Vet Med Assoc. 224:

1123-7

7. French K, Pollitt CC, Pass MA. 2000 Pharmacokinetics and metabolic effects of triamcinolone acetonide and their possible relationships to glucocorticoid- induced laminitis in horses. J Vet Pharmacol Ther. 23(5):287-92.

8. Karikoski NP, Horn I, McGowan TW, McGowan CM. 2011 The prevalence of endocrinopathic laminitis among horses presented for laminitis at a first opinion/ referral equine hospital. Dom anim Endocr 41: 111–7

9. McGowan CM, Frost R, Pfeiffer DU, Neiger R. 2004 Serum insulin concentrations in horses with equine Cushing's syndrome: response to a cortisol inhibitor and prognostic value. Equine Vet J. 36(3):295-8.

10. Pass, M.A., Pollitt, S. and Pollitt, C.C. (1998) Decreased glucose metabolism causes separation of hoof lamellae in vitro: a trigger for laminitis? Equine vet. J., Suppl. 26, 133-138.

11. Tiley HA, Geor RJ, McCutcheon LJ. 2007 Effects of dexamethasone on glucose dynamics and insulin sensitivity in healthy horses. Am J Vet Res. 68(7):753-9.

12. Tinworth KD, Raidal SL, Harris PA, Sillence MN, Noble GK. 2011 Comparing glycaemic and insulinaemic responses of ponies and horses to dietary glucose (abstr.) Journal of Equine Veterinary Science 31, 301

13. Tóth F, Frank N, Martin-Jiménez T, Elliott SB, Geor RJ, Boston RC. 2010 Measurement of C-peptide concentrations and responses to somatostatin, glucose infusion, and insulin resistance in horses. Equine Vet J. 42(2):149-55.

14. Venugopal CS, Eades S, Holmes EP, Beadle RE. 2011 Insulin resistance in equine digital vessel rings: an in vitro model to study vascular dysfunction in equine laminitis. Equine Vet J. 43(6):744-9.

15. Walsh, D.M., McGowan, C.M., McGowan, T., Lamb, S.V., Schanbacher, B.J. and Place, N.J. (2009) Correlation of Plasma Insulin Concentration with Laminitis Score in a Field Study of Equine Cushing's Disease and Equine Metabolic Syndrome. J Equine Vet Sci 29, 87-94.

16. Wattle, O. and Pollitt, C.C. (2004) Lamellar metabolism. Clin. Tech. equine Pract. 3, 22-33.

Vet Sci 29, 87-94. 16. Wattle, O. and Pollitt, C.C. (2004) Lamellar metabolism. Clin. Tech. equine

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hOw tO UNDErStAND AND rECOgNISE LAMINItIS Of ENDOCrINE OrIgIN

Andy Durham BSc.BVSc.CertEP.DEIM.DipECEIM.MRCVS

The Liphook Equine Hospital, Forest Mere, Liphook, Hampshire, GU30 7JG, UK. andy@TheLEH.co.uk Tel 0044 1428 723594 Fax 0044 1428 722263

This presentation will discuss the causation of EMS and PPID, the primary conditions associated with endocrinopathic laminitis, and also the clinical presentation and recognition of endocrinopathic laminitis. Separate presentations discuss the pathophysiology of endocrinopathic laminitis (Laminitis an Inflammatory or endocrine disease?) and the laboratory diagnosis of these conditions.

whAt IS EqUINE MEtABOLIC SyNDrOME?

As metabolic syndrome has progressed into the greatest threat to human health in the developed world in association with readily available, highly caloric food and drink and a more sedentary lifestyle [1], a broadly analogous concern has developed in horses associated with more generous and relaxed feeding and management practices. In 1988 Reaven published his observation that many human patients suffering from cardiovascular disease had, at the same time, glucose intolerance, hyperinsulinaemia, hypertriglyceridaemia, low HDL-cholesterol and hypertension [2]. He considered that insulin resistance (IR) was the driving force for this syndrome. In 2002 Johnson also noted that many equine patients suffering from laminitis shared similar features and first proposed the term equine metabolic syndrome (EMS) [3] and working definitions have been proposed that comprise markers of obesity, IR and dyslipidaemia [4,5]. Twenty- five years on from its initial description, the metabolic syndrome in humans continues to provoke debate not only regarding its pathophysiology, treatment and management, but also even regarding its fundamental definition and clinical relevance [6]. It should come as no surprise then that the much newer concept of EMS will continue to develop and evolve as new insights and research findings are presented [7].

much newer concept of EMS will continue to develop and evolve as new insights and research

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Both human and equine metabolic syndromes are primarily created and maintained by chronically excessive caloric intake and physical inactivity with further important and related susceptibility factors also being involved. The major defining clinical consequence of EMS is laminitis although it is possible that further pathogenetic endpoints may become better recognised in the future. Thus, for the time being at least, EMS might be regarded as a collection of coexisting risk factors, associated with metabolic and endocrine dysregulation, that signal an increased susceptibility to laminitis”. Thus far, identifiable risk factors that may alert the clinician to the presence of EMS comprise several endogenous phenotypic characteristics along with further important interactive and influential exogenous factors (table 1). The main laminitis risk factor omitted from table 1 is pituitary pars intermedia dysfunction (PPID) and this will be discussed separately (see later).

Table 1. Candidate risk factors defining EMS and associated risk of laminitis. PPID is not strictly part of the definition of EMS but is included as a further prominent risk factor for laminitis.

Endogenous

Exogenous

Signalment

Clinical

Clinicopathological

age

obesity

dysinsulinaemia

little exercise

breed

previous laminitis

dyslipidaemia

dietary excess

gender

(PPID)

abnormal adipokines

season

IDENtIfICAtION Of ANIMALS At rISk Or EXhIBItINg SIgNS Of LAMINItIS IN ASSOCIAtION wIth EMS

Cases of EMS are usually first recognised and investigated following a diagnosis of laminitis. Hopefully in the future with more widespread awareness of the syndrome, more cases will be seen in a pre- or sub-clinical laminitic stage where risk factors are recognised and control measures are implemented before clinical disease occurs. Early recognition of EMS should therefore be encouraged by client education and preventative health care programmes. Dysregulation of insulin (dysinsulinaemia) may represent a key pathophysiological driving force for EMS, with obesity and laminitis being the most prevalent clinical manifestations.

The recognition of clustering of common risk factors (table 1), which led to the initial syndromic proposals [2,3], is essential for the identification and differentiation of EMS from other causes of laminitis. For example, when we see laminitis that is recurrent in a 9 year old, obese, native pony, whilst grazing, in May, that is exercised very little, and further diagnostic testing indicates dysinsulinaemia and dyslipidaemia, then we suspect EMS.

exercised very little, and further diagnostic testing indicates dysinsulinaemia and dyslipidaemia, then we suspect EMS. 20

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How to understand and recognise laminitis of endocrine origin

On the other hand, laminitis caused by excessive load-bearing (supporting limb laminitis), grain engorgement, retained foetal membranes, colon torsion or acute colitis may be less epidemiologically distinct and affect a far more diverse range of individuals that may be younger, leaner, fitter, of any breed, at any time of year, not grazing, with no prior history of laminitis and no predisposing clinicopathologic features. Further discussion of recognisable factors that should lead to suspicion and/or diagnosis of EMS follows.

SIgNALMENt ChArACtErIStICS Of EMS CASES

Age

EMS is typically identified from 5-8 years of age [3,7] recognising an apparently decreased susceptibility of young horses to laminitis [5,8-10]. Anecdotally many young ponies are seen to become obese in the first 2-5 years of life although limited opportunities and owner requests arise to perform further investigation of such individuals usually until after laminitis has occurred, sometimes years later. Longitudinal studies, starting in foal-hood, that describe the age of onset and development of risk factors for laminitis susceptibility later in life (e.g. obesity, dysinsulinaemia) have not been published and many identifiable components of EMS might occur in young horses a long time before clinical laminitis is recognised.

The precise reason for the apparently decreased risk of laminitis in young horses is not apparent although reduced prevalence of excessive adipose deposits in an actively growing individual with higher caloric requirements along with often higher levels of voluntary physical activity may all play a role. Age effects on IR per se have not been well described in horses although one study found that 6-9 month old foals had reduced glucose tolerance (implying relatively greater IR) compared to mature ponies [12] suggesting that insulin sensitivity is not a protective mechanism that explains reduced prevalence of laminitis in young animals.

Animals older than 15-18 years of age are also less commonly affected by EMS [3,7] perhaps as a result of a relatively increased prevalence of PPID-related laminitis in an older age-group [11]. Even in the absence of PPID, decreased adiposity associated with age-related disease such as dental disorders may also be protective against EMS in older horses.

gender

Some studies have indicated that mares and stallions may be more prone to laminitis than geldings [10,13-15]. Any apparent gender effect could be confounded by several other factors such as physical activity, likelihood of seeking veterinary attention, body condition and insulin sensitivity. Decreased insulin sensitivity in females was suggested by one study of hyperlipaemia in donkeys [16].

sensitivity. Decreased insulin sensitivity in females was suggested by one study of hyperlipaemia in donkeys [16].

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Breed/type

It is recognised that certain “easy-keeping” or “good-doing” equine breeds are inherently prone to laminitis such as Shetland, New Forest, Dartmoor, Exmoor, Welsh, Morgan, Tennessee Walking horse, Quarterhorse, Paso Fino, Arabian, Saddlebred, Spanish Mustang and donkeys [7,10,13]. There may be external managemental influences to consider in the type and level of activity commonly associated with typical EMS breeds, although it is also likely that retention of certain “thrifty” genes are also important [17]. Several genetic traits may once have provided a survival advantage to ancestors that evolved and adapted to survive well in harsh environments where dietary energy supply was variably accessible due to seasonal drought or cold. The ration would generally comprise low energy density, low non-structural carbohydrate (NSC), high-fibre, food sources. Numerous physiologic and metabolic adaptations may be inherent in such individuals such as increased appetite for food when available, greater assimilative capacity from ingested food and altered metabolic/endocrine responses to assimilated nutrients. The most prominent metabolic/endocrine differences between laminitis-prone horses and non-laminitic individuals involve dysregulation of insulin. The concept of a primary tendency towards either IR or hyperinsulinaemia makes sense in evolutionary terms. Many breeds known to be prone to laminitis evolved in nutritionally sparse environments where food supply may have been both poor and inconsistently available. Evolutionary development of relative resistance to the effects of insulin would have the metabolic advantages of prioritisation and preservation of glucose for non-insulin dependent tissues such as the brain, kidneys, heart and laminae, and additionally the capacity to more rapidly mobilise glycogen and adipose stores when feed becomes unavailable (eg. during drought or snow). Evolutionary development of a tendency towards hyperinsulinaemia is also logical. In harsh environments ingestion of significant amounts of nutrients that stimulate insulin secretion such as glucose would be a relatively rare event. Under such circumstances individuals may have developed a relatively decreased beta-cell threshold for glucose-induced insulin secretion (otherwise insulin would never be secreted!) which then becomes overstimulated resulting in excessive hyperinsulinaemia when exposed to diets typical of modern domesticated horses and ponies.

The recognition of particular breeds and types prone to obesity and laminitis is suggestive of genetic determination of some risk factors at least. Ponies have long been known to be inherently insulin resistant when compared to horses [18-21] and a study of an inbred closed pony herd in Virginia revealed strong genetic influences on laminitis occurrence [4]. These same individuals are also known to secrete more insulin in response to oral sugar challenges (see “Laminitis an Inflammatory or endocrine disease?”). Complex and polygenic influences on many aspects of ingestive and exertional behaviours, digestive physiology, endocrinology and nutrient and adipose metabolism may well all play a role in EMS.

behaviours, digestive physiology, endocrinology and nutrient and adipose metabolism may well all play a role in

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CLINICAL ChArACtErIStICS Of EMS CASES

Laminitis characteristics in EMS cases

When a middle-aged, obese, sedentary native pony is grazed simultaneously on the same pasture as a fit, lean, young Thoroughbred, then only the former is likely to develop laminitis; implying differing physiologic/metabolic/endocrine responses to the ingested nutrients. Recent studies have suggested that endocrinopathic mechanisms may be

important predisposing factors in approximately 90% of clinical laminitis cases [22,23],

a figure that at first glance might seem surprisingly high. However, for far longer than

the recent discussions of endocrinopathic laminitis, veterinarians and horse owners have recognised that many laminitis-prone individuals share similar characteristics such as breed, age, obesity, a rich-diet and low-workload (table 1). Conversely they would also recognise that laminitis arising in the absence of these factors is relatively unusual (i.e. less than 10% of cases!).

Thus when considering the clinical examination and characteristics of the affected feet of animals with EMS-related laminitis, there are no special or unusual distinguishing features on which to comment as, alongside PPID, they probably constitute the regular, every-day cases that we all see [22,23]. They may present with forelimb and/ or hindlimb signs, mild or severe pain, with acute onset signs or with mild to severe chronic anatomic foot abnormalities such as prominent and divergent hoof rings, concavity of the dorsal hoof wall, expansion of the white line and solar flattening or convexity [24,25]. Clearly laminar pain and cohesive failure is not an “all-or-nothing” event and detectable anatomic changes may be seen (e.g. growth rings, expansion of white line) in the absence of a history of obvious foot pain, perhaps relating to a low grade, chronic and insidious laminar disease process [3].

Chronicity and recurrence are frequent features of EMS-related laminitis [3-5,7]. Fundamentally there are probably 2 reasons why cases of laminitis might recur:

firstly, that damage caused by previous disease episodes makes the foot inherently more susceptible to further laminitis attacks; and secondly, that the endogenous and exogenous risk factors associated with the previous laminitis episode (e.g. IR, obesity, excessive grazing) are still present. Indeed, a common question from the owner of a de novo laminitic animal is “will this mean that my pony will always

continue to suffer from laminitis?”. It is obvious that recurrence should be expected

in those cases where the fundamental causal factors are not subsequently managed

and controlled effectively. It is therefore vital that laminitis cases encountered in practice are not simply treated and managed for laminitis in an isolated fashion, but that epidemiology is considered thoroughly so that identification and control of significant risk factors can be instigated. This comprises investigation of historical, clinical and clinicopathologic factors (table 1).

can be instigated. This comprises investigation of historical, clinical and clinicopathologic factors (table 1). 23

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Obesity

Obesity has long been associated with laminitis-susceptibility and is a prominent epidemiologic feature of EMS [4,5,10,26] and human metabolic syndrome [6]. The precise links between obesity and laminitis are not fully understood but a causal association with IR is a likely candidate [19,27-29].

It has been estimated that around half of the horses in the UK are overweight [30-31]. Obesity is a contentious and emotive term that is surprisingly poorly recognised for what is commonly, but not invariably, an externally obvious sign. Several studies have shown that owners of many obese horses do not appear to recognise its existence in their animals [30-32]. One might surmise that this could represent “denial” on the part of the owner; a defensive psychological response to avoid dealing with a problem that they find impossible to manage. Alternatively it may be that many horse owners have become gradually accustomed to a slowly increasing degree of adiposity in their horses, perhaps encouraged by judges in some equestrian disciplines who actively select and reward animals carrying externally obvious excessive adipose tissue. However, a further possible source of misconception is a lack of understanding about what obesity actually is.

Obesity is broadly defined in a medical context as “excessive adiposity to an extent where health is negatively affected”. Obesity is therefore primarily a functional and metabolic status, rather than simply a morphological status, and may not always directly correlate with the size of adipose deposits [33]. In contrast, in general colloquial parlance obesity may be defined entirely according to visual preconceptions that obese individuals will represent the extreme of excess bodily condition manifesting as a severe degree of adipose coverage over the entire body. Indeed, laminitis-prone individuals are often overtly and unequivocally morphologically obese with an absence of palpable ribs, large fatty deposits behind the shoulders and tail-head and a large firm crest. However, others may have palpable or even visible ribs leading some to describe them as “lean”, although retaining a large cresty neck or perhaps hidden deposits of retroperitoneal fat. The point at which an individual’s health becomes compromised by the presence of adipose deposits (i.e. when obesity develops) is variable and dependent on the amount, the site and the metabolic activity of adipose tissue in that individual, emphasising the importance of “regional obesity”. In human patients there is substantial evidence indicating that fat distribution is a better predictor of cardiovascular disease than overall fat volume [34,35]. Uneven development and disappearance of regional adipose deposits in horses and ponies is also well described [36]. Two published studies have specifically proposed clusters of risk factors defining EMS [4,5] and both included markers of regional adiposity (Table 2).

proposed clusters of risk factors defining EMS [4,5] and both included markers of regional adiposity (Table

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How to understand and recognise laminitis of endocrine origin

Table 2. Proposed working definitions of EMS. Laminitis susceptibility is defined when at least 3 of the 4 listed factors are identified [4,5]. BCS= Body Condition Score; CNS=Cresty Neck Score.

At least 3 of the following [from reference 4]:

BCS 7 with localized fat deposits on neck and tailhead

Reverse inverse square of insulin < 0.32 [mU/L] 0.5

Modified insulin response to glucose > 5.6 mU insulin 2 /[10•L•mg glucose]

Triglyceride concentration > 57.0 mg/dL

glucose] Triglyceride concentration > 57.0 mg/dL BCS ≥ 7 CNS ≥ 4 Insulin > 32 mU/L

BCS 7

CNS 4

Insulin > 32 mU/L

Leptin > 7.3 ng/mL

Unfortunately the definition of excessive adiposity in an individual when seen by a practitioner is usually based on a subjective opinion, a situation that does not facilitate the conversion of sceptical horse owners who do not believe that their animal is obese. Body mass index (body mass/height 2 ) has been described in horses as a possible objective index of adiposity, although has received little attention [37]. The lack of widespread availability of weighbridges does not, in any case, encourage the use of any index relating to body mass.

Body condition scoring (BCS) is perhaps the most frequently used semi-objective index of obesity although generally still lacks widespread acceptance and usage in practice and may require tailoring for different breeds, ages, genders and activities [21]. Lack of clarity and user-friendliness is not aided by confusing and poorly defined descriptive terminology that is hard to apply, requiring the user to distinguish fat deposits that feel “spongy”, “soft”, very soft”, “patchy” or “bulging” [38]. Nevertheless BCS has been shown to correlate well with markers of IR and laminitis susceptibility [5,21,26] and one study found that BCS >6.8 was a good indication that total body fat content exceeded 20% [39]. The “cresty-neck score” (CNS) is a semi-objective means of describing regional obesity with respect to the apparently particular associations between crest fat, IR and laminitis [5,21] (Table 3). However, again breed, gender and perhaps age effects are also important with interpretation as one study found that associations between both BCS and CNS with hyperinsulinaemia was only significant for ponies and not for horses [21].

associations between both BCS and CNS with hyperinsulinaemia was only significant for ponies and not for

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Table 3. Cresty neck score [21]

0 No visual appearance of a crest.

No palpable crest

1 No visual appearance of a crest, but slight filling felt with palpation

2 Noticeable appearance of a crest, but fat deposited fairly evenly from poll to withers.

Crest easily cupped in one hand and bent from side to side

3 Crest enlarged and thickened, so fat is deposited more heavily in middle of the neck than toward poll and withers, giving a mounded appearance.

Crest fills cupped hand and begins losing side to side flexibility

4 Crest grossly enlarged and thickened, and can no longer be cupped in one hand or easily bent from side to side.

Crest may have wrinkles/creases perpendicular to topline

5 Crest is so large it permanently droops to one side

Practical and objective morphometric measures of both abdominal/trunk fat (girth:height ratio, waist:height ratio) and crest fat (crest height, neck circumference, neck circumference:height ratio) have been described by several studies and related to other markers of obesity, IR and laminitis [5,21,26,38]. However, it has been found that these objective morphometric measures are generally less strongly correlated with body fat percentage and serum biochemical indices of IR than are the semi-objective BCS and CNS [21,38]. Nevertheless, given the obvious attraction of objectivity, it has been suggested that certain cut-offs of morphometric measures could be used in ponies and horses to indicate overweight, obesity and crestiness (Table 4). Indeed in one large study of a particular pony herd, laminitis was predicted with reasonable accuracy in ponies with a girth:height ratio >1.30 and neck circumference:height ratio > 0.71 [5].

Table 4. Suggested objective morphometric measurements indicative of excessive adiposity in horses and ponies [21] (0.5NC = mid-neck circumference)

Pony

horse

Overweight

Girth:height 1.33

Girth:height 1.26

Obese

Girth:height 1.38

Girth:height 1.29

Cresty

0.5NC:height 0.68

0.5NC:height 0.63

Girth:height ≥ 1.38 Girth:height ≥ 1.29 Cresty 0.5NC:height ≥ 0.68 0.5NC:height ≥ 0.63 26

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Fat depth measured ultrasonographically in specific areas such as shoulder, intercostal space, rump and retroperitoneal layer, might have potential to be used as a further objective measure of adiposity [36,39,40]. One study suggested that percentage total body fat could be estimated by the formula 8.64 + (4.7 x rump fat thickness [cm]) in horses and 3.83 + (5.58 x rump fat thickness [cm]) in ponies [36]; whereas another derived a slightly different formula (% fat = 2.47 + (5.47 x rump fat thickness [cm]) although breeds were not specified [41].

Experience suggests that with the exception of many PPID cases, it is rare to encounter

a laminitis-prone individual where it would be unequivocally wrong to encourage further

weight loss, although such cases do exist. To describe a laminitis-prone individual as “non-obese” requires confidence that the fat deposits, which every individual will inevitably

have (and may well be only present in certain places), are playing no direct or indirect role

in the disease process.

hypertension

Hypertension is a central feature of the metabolic syndrome in people but has received little attention in horses, perhaps due to relative inconvenience and lack of blood pressure measurement as part of a standard clinical examination of the horse. Clinical laminitis has long been recognised as a hypertensive disease and several anti-hypertensive therapies have been advocated [42]. However, whether or not hypertension is a pathogenetic factor or simply a secondary consequence of the pain and distress associated with acute laminitis is not known. Interestingly, one study found that laminitis-prone ponies had higher mean blood pressure in the summer than non-laminitic controls even when not clinically affected, supporting hypertension as a candidate marker for laminitis-susceptibility in a striking analogy with cardiovascular-risk in the human metabolic syndrome [43]. However, other studies have not confirmed this finding [5].

fUrthEr EXOgENOUS fACtOrS COMMONLy IDENtIfIED IN EMS CASES

Dietary quality and quantity

Dietary intake is a key factor determining laminitis susceptibility and also represents a frequently recognised final trigger event. Many EMS cases with laminitis have a long-term history of chronic caloric overprovision and a short-term history of ingestion of a high NSC diet (usually grazing).

Chronic overprovision of dietary calories is the fundamental cause of adipose expansion which may culminate in obesity, a key risk factor for laminitis. Prediction and determination of caloric requirements is always approximate and clearly depends on metabolic activity

Prediction and determination of caloric requirements is always approximate and clearly depends on metabolic activity 27

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relating to exercise, growth, pregnancy and lactation, and it is now further recognised that there are fundamentally different energy requirements of individual animals in concordance with the anecdotal observations of “easy-keepers” and “good-doers” [49]. Metabolic efficiency is frequently used as an excuse for an inability to control obesity in laminitis-prone individuals, and it is clearly evident that weight loss is hard to achieve in such animals. However, to suggest that obesity is absolutely resistant to dietary caloric restriction is illogical; it is simply a question of how severe the restriction needs to be. It is inconceivable that turning out an obese native-breed animal to join its feral desert- living counterparts for example, would result in long-term maintenance of its obesity! Weight loss achieved by diet and exercise is associated with improved insulin sensitivity in horses [28,29,40], and, by implication, decreased risk of laminitis. There is some evidence that dietary composition may also be an important determinant of IR in that insulin responsiveness was found by one study to be lower in horses receiving high NSC diets than high fat and fibre diets [27].

Given the likely pathogenic importance of hyperinsulinaemia as an acute trigger factor for laminitis [50-52], it is logical to assume that highly insulinaemic diets will represent an immediate risk of laminitis. Non-structural carbohydrates comprise simple sugars, starches and fructans and pose the greatest insulinaemic potential although the possible insulinaemic effect of other components such as amino acids in equine feeds has received little attention. Simple sugars and digestible starches clearly pose a high risk of hyperinsulinaemia and form the bulk of the NSC within cereals (typically 50-70% DM) and leguminous pastures (typically 10-20% DM). Fructans are the major storage carbohydrate in temperate grasses and exist alongside simple sugars as water soluble carbohydrate (WSC) in non-leguminous pastures, hays and silages (typically 10-20% DM). Although fructans are regarded as indigestible by the horse, bacterial hydrolysis to fructose and glucose within the equine upper gastrointestinal tract may provide an explanation for hyperinsulinaemia following fructan ingestion [53-55]. One UK study found that serum uric acid, a metabolite of fructose, was found in slightly higher concentrations in laminitis- prone ponies compared to normal ponies during the summer [43] although this was not confirmed by a further study in the USA [21].

The majority of EMS-related laminitis appears to follow grazing although some might relate to cereal feeding. The traditional explanation for this apparent link was that NSC ingested in excess of the digestible (or hydrolysable) capacity of upper gastrointestinal tract, led to rapid caeco-colonic fermentation, dysbacteriosis, acidosis, mucosal barrier compromise and systemic absorption of toxic laminogenic trigger factors, as demonstrated by the experimental model of starch (or fructan) overload [56]. However, it is inconceivable that under normal management conditions NSC ingestion equivalent to the starch/fructan overload model (5-10 g NSC/kg BWT bolus) could occur, except perhaps in rare cases of cereal feeding accidents. Although grazing ponies may eat as much as 10 g DM/kg BWT in a 3 hour grazing period [57], even given an extreme example of grass NSC content of 40% DM it is apparent that intake of more than 1-2 g NSC/kg BWT per hour is implausible; and far lower rates of intake (<0.5 g NSC/kg BWT/hour) are more probably representative

per hour is implausible; and far lower rates of intake (<0.5 g NSC/kg BWT/hour) are more

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of realistic grazing activity. The demonstration of marked hyperinsulinaemia in association with gradual ingestion of NSC at rates lower than this [54,58] represents a more plausible endocrinopathic link between grazing and laminitis.

Season

Laminitis has a strong seasonal incidence that has been demonstrated by several studies. The majority of non-PPID laminitis cases seen in temperate climates arise in late Spring/ early summer [8,13,15], perhaps as a result of increased pasture NSC content leading to pathologic hyperinsulinaemia [5]. In addition to seasonally variable NSC ingestion, there may be additionally seasonally differing responses to ingested NSC although one recent study found insulin responses to ingested carbohydrate in laminitis-prone ponies to be higher in October/November versus May/June, contrary to expectations [55]. Significant monthly variability in resting insulin concentrations in both normal and EMS cases was demonstrated in one study but this showed no distinct seasonal pattern [59]. An increased incidence of PPID-related laminitis in the autumn has been suggested in accordance with increased pituitary secretory activity at that time in PPID cases [22]. However, it is known that pars intermedia secretory activity is also augmented in the autumn in horses without PPID [59-61] and the possible endocrinopathic consequences of this observation on EMS cases may warrant further investigation.

workload and activity

Many laminitis cases are relatively sedentary animals participating rarely, if at all, in organised exercise activities [10]. Enforced stable confinement is a common part of acute and chronic laminitis management for the purposes of preservation of laminar integrity and/or grazing restriction and this further adds to the lack of physical activity that typifies these animals. Conversely, it is a common anecdotal observation that fit, working ponies are generally less prone to laminitis. Perhaps the most obvious potential explanation for the apparent negative association between exercise and laminitis relates to obesity and that the increased caloric demands of exercise mitigate against dietary overprovision as discussed above. However, there may be additional benefits of exercise on metabolism or even, conceivably, on laminar cohesive strength as an adaptive response to mechanical stresses as seen in most other orthopaedic tissues. In other species a positive effect of exercise on insulin sensitivity is recognised independently of adiposity [62]. Several studies have also examined the effects of various exercise regimes on insulin sensitivity in horses and, although generally supportive of a beneficial effect of exercise, this has not been a consistent finding [63-66]. Whether or not such an effect exists, there are almost certainly further benefits of exercise that are likely to help reduce on-going laminitis risk and therefore activity should be encouraged wherever laminar integrity and comfort so allow.

on-going laminitis risk and therefore activity should be encouraged wherever laminar integrity and comfort so allow.

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38. Henneke DR, Potter GD, Kreider JL, Yeates BE. 1983 Relationship between condition score, physical measurement and body fat percentage in mares. Equine vet. J. 15: 371-2

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42. Hinckley KA, Fearn S, Howard BR, Henderson IW. 1996 Nitric oxide donors as treatment for grass induced acute laminitis in ponies. Equine Vet J. 28: 17-28

IW. 1996 Nitric oxide donors as treatment for grass induced acute laminitis in ponies. Equine Vet

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43. Bailey SR, Habershon-Butcher JL, Ransom KJ, Elliott J, Menzies-Gow NJ. 2008 Hypertension and IR in a mixed-breed population of ponies predisposed to laminitis. Am J Vet Res. 69: 122-9

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46. Sessions DR, Reedy SE, Vick MM, Murphy BA, Fitzgerald BP. 2004 Development of a model for inducing transient insulin resistance in the mare: preliminary implications regarding the estrous cycle. J Anim Sci. 82: 2321-8

47. Vick MM, Sessions DR, Murphy BA, Kennedy EL, Reedy SE, Fitzgerald BP. 2006 Obesity is associated with altered metabolic and reproductive activity in the mare:

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48. Rambags BP, van Rossem AW, Blok EE, de Graaf-Roelfsema E, Kindahl H, van der Kolk JH, Stout TA. 2008 Effects of exogenous insulin on luteolysis and reproductive cyclicity in the mare. Reprod Domest Anim. 43: 422-8

49. National Research Council 2007 Energy. In: Nutrient Requirements of Horses, 6th edition. Washington: National Academies Press. p 3-33

50. Asplin KE, Sillence MN, Pollitt CC, McGowan CM. 2007 Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies. Vet J. 174: 530-5

51. de Laat MA, McGowan CM, Sillence MN, Pollitt CC. 2010 Equine laminitis: induced by 48 h hyperinsulinaemia in Standardbred horses. Equine Vet J. 42: 129-35

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55. Borer KE, Bailey SR, Menzies-Gow NJ, Harris PA, Elliott J. 2012 Effect of feeding glucose, fructose, and inulin on blood glucose and insulin concentrations in normal ponies and those predisposed to laminitis J Anim Sci. (in press)

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59. Place NJ, McGowan CM, Lamb SV, Schanbacher BJ, McGowan T, Walsh DM. 2010 Seasonal variation in serum concentrations of selected metabolic hormones in horses. J Vet Intern Med. 24: 650-4

60. Donaldson MT, McDonnell SM, Schanbacher BJ, Lamb SV, McFarlane D, Beech J. 2005 Variation in plasma adrenocorticotropic hormone concentration and dexamethasone suppression test results with season, age, and sex in healthy ponies and horses. J Vet Intern Med. 19: 217-22

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whAt IS PItUItAry PArS INtErMEDIA DySfUNCtION (PPID)?

PPID is a common equine endocrine disorder although is still poorly understood with respect to the relevant secretory products and their effects. The secretory capacity of

the pars intermedia in a normal horse is autonomously active and is controlled by chronic inhibition by dopaminergic neurons from the hypothalamus. The primary pathophysiologic event in PPID is oxidative damage to these tonic inhibitory dopaminergic neurons leading

to hypersecretion of the uninhibited pars intermedia, hypertrophy, hyperplasia and

possibly micro- and macro-adenoma development within the pars intermedia (Miller et al 2008). Endocrine cells within the pars intermedia (known as melanotropes) synthesise

a 241-aminoacid polypeptide called pro-opiolipomelanocortin (POMC). Through a

combination of gene expression and proteolytic cleavage by prohormone convertases 1/3 and 2, several smaller peptides can be produced mainly comprising adrenocorticotrophic hormone (ACTH), a, b and g-melanocyte stimulating hormone (a, b, g-MSH), corticotropin- like intermediate lobe peptide (CLIP), b and g-lipotropin and b-endorphin (Wardlaw 2011). The primary products of the PI in normal horses comprise a-MSH and CLIP whereas, additionally, production of ACTH occurs in the presence of PPID (Orth et al 1982; Orth and Nicholson 1982; Wilson et al 1982).

The main source of ACTH in the normal equine pituitary gland however is the pars distalis which is unaffected in PPID. Only the pars distalis is subject to negative feedback by endogenous cortisol or exogenous glucocorticoid drugs which subsequently lead to

suppression of cortisol secretion when administered to normal horses. Understanding of the relationship between the dysfunctional, hypersecretory pars intermedia in PPID cases with the adrenal axis is slightly confusing. On the one hand exogenous dexamethasone administration in PPID cases tends to fail to suppress endogenous cortisol suggesting that cortisol secretion and adrenal activity is maintained by pars intermedia derived peptides such as ACTH, perhaps augmented by a synergistic adrenocorticotrophic effect of a MSH and b endorphin. On the other hand several studies indicate that ACTH secreted in PPID is significantly less bioactive than normal ACTH and consequently adrenal hypertrophy and hypercortisolaemia are not generally seen. A further product of the pars intermedia is b-cell tropin and this may have the additional effect of stimulation of pancreatic b-cells

to secrete insulin.

CLINICAL ChArACtErIStICS Of PPID CASES

The oxidative damage to hypothalamic neurones which precedes development of PPID in horses is intuitively age-related and undoubtedly PPID is more prevalent in older horses. However, this fact is frequently misconstrued to indicate falsely that PPID does not occur in young horses. Yet it is not difficult to find publications describing post-mortem confirmed PPID in horses as young as 7 to 8 years of age. An inherent bias towards clinical suspicion of PPID in older horses with well-developed clinical characteristics may have served to limit recognition of the disease in younger age groups, perhaps at an earlier

characteristics may have served to limit recognition of the disease in younger age groups, perhaps at

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clinical (or even sub-clinical) stage with fewer, if any, clinical indications of PPID. Recent data derived from more speculative testing for PPID as a result of a subsidised testing scheme (“Talk About Laminitis”, Boehringer Ingelheim) indicated that a significant number of horses testing positive for PPID were below the age of 10 years and frequently showed no clinical signs other than laminitis. Thus, it may well be that preconceived attitudes towards the typical age and clinical signs of PPID cases better relates to progressed or even end-stage disease, rather than possibly more typical early clinical or subclinical disease. At the very least, the idea should be entertained that many PPID cases may exist in younger horses that might not demonstrate what are regarded as typical or prominent clinical signs. Indeed data derived from ante- and post-mortem examination of 72 PPID cases suggests that approximately 80% of PPID cases may demonstrate few if any clinical signs (D.McFarlane, data presented at ACVIM forum 2012).

Alteration in hair growth is frequently associated with clinical PPID. An excessive and curly hair coat, or hypertrichosis, is typical of older, perhaps end-stage cases whereas earlier cases may simply demonstrate delayed seasonal shedding or retention of some longer hairs interspersed in an otherwise normal hair coat. The causal mechanism for this prominent sign is unknown although seasonal pituitary hyperactivity seen in normal horses prior to onset of winter perhaps relates to a milder physiologic stimulation of hair growth, of which PPID represent a more extreme pathologic version.

Laminitis is probably the most clinically concerning feature of PPID and is responsible for the majority of decisions for euthanasia of PPID cases. In a recent Australian study it was estimated that 13% of PPID cases over the age of 15 years suffered from laminitis, compared with 3% of age-matched non-PPID cases (McGowan et al). Although, on the one hand this indicates that PPID represents an almost 5 times increased risk of laminitis, it is also evident that many PPID cases do not suffer from laminitis. However, it is also not unlikely that additional cofactors that are more prominent in other countries such as lush grazing could add to the risk that PPID represents. Additionally further evidence suggests that younger PPID cases are more likely to suffer from laminitis than older cases (A. Durham, unpublished data) which may have led to an underestimate of laminitis prevalence by the age-restricted Australian study above.

Polydipsia / Polyuria is a reasonably prominent feature of many cases but is not always well recognised by the owner. The precise cause is unclear and perhaps variable. Although it may result from direct glucocorticoid effect on the renal tubules, there is generally no evidence of hypercortisolaemia in PPID cases. Altervative causes include diabetes insipidus from interference with vasopressin synthesis /release, or as a consequence of insulin resistance and type 2 diabetes mellitus.

Lethargy is commonly present in PPID cases but not always well recognised as the owners might be forgiven for supposing lethargy is simply associated with old age. Nevertheless the frequent improvement in this clinical sign in response treatment suggests that it is genuinely present although the cause is, again, unclear.

this clinical sign in response treatment suggests that it is genuinely present although the cause is,

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How to understand and recognise laminitis of endocrine origin

Excessive sweating is a fairly well recognised feature, the cause of which is not entirely clear but may be related to dysregulation of thermal homeostasis and / or the potentiating effect of glucocorticoids on adrenoceptors in sweat glands. This clinical sign is particularly prominent associated with pain (e.g. laminitis) or sedation (e.g.  2 agonists) in PPID cases.

Fat redistribution is often evident in two manifestations. Firstly a general potbellied appearance and secondly with fat redistribution around the eyes. Although this latter feature has commonly been described as an increase in supraorbital fat pads, this is not always the case and there can also be a frequent finding of “bags under the eyes” and partial prolapsed of the 3 rd eyelids.

Susceptibility to Infection is an unusual consequence of PPID. Occasional cases are seen with, for example, recurrent sheath infections, mastitis, or bronchopneumonia. Increased susceptibility to parasitism has however been proven.

Weight loss might occur due to PPID, but this is generally not marked unless diabetes mellitus develops or further unrelated issues arise such as dental disease etc

Neurological signs have rarely been reported in PPID cases, presenting with perhaps blindness, collapse or seizures presumably associated with increased pressure on the base of the brain associated with the expanding pituitary gland.

SUMMAry

The majority of cases of laminitis seen in practice have an underlying endocrine basis. They are likely to share common features in respect of readily detectable endogenous and exogenous risk factors. Paramount amongst the controllable and reversible risk factors are PPID, over-feeding, lack of exercise, obesity and insulin resistance. Equine metabolic syndrome describes the clustering of some of these factors and, if persistent recurrence of laminitis is to be avoided, it is essential that they are identified and controlled wherever possible. However, a more ideal aspiration would be to identify and control these risk factors in young animals before the initial onset of the laminitis that they predict.

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45. Rohrbach, B.W., Stafford, J.R., Clermont, R.S.W., Reed, S.M., Schott II, H.C., and Andrews, F.M. (2012) Diagnostic frequency, response to therapy, and long-term prognosis among horses and ponies with pituitary par intermedia dysfunction, 1993 –2004. J Vet Intern Med 26, 1027–1034

46. Schott, H.C. (2002) Pituitary pars intermedia dysfunction: equine Cushing’s disease. Vet Clin North Am Equine Pract 18, 237-270

47. Schott, H.C., Coursen, C.L., Eberhart, S.W., Nachreiner, R.J., RefsalK.R., Ewart, S.L. and Marteniuk, J.V. (2001) The Michigan Cushing's Project. Proceedings American Association of Equine Practitioners 47, 22-24.

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48. Schott, H.C., Eberhart, S.W., Nachreiner, R.F. and Beyerlein, S. (2007) Effect of season on overnight dexamethasone suppression test results in aged horses without clinical signs of pituitary pars intermedia dysfunction (abstr). Veterinary Dermatology 18, 193.

49. Schott, H.C., Schenck, P. and Refsal, K. (2012) Comparison of assay kits for measurement of plasma adrenocorticotropin concentration. Abstract Equine Endocrinology Summit, Boston.

50. Sommer K. (2003) Das Equine Cushing-Syndrom: Entwicklung eines ACTH- Bioassays für die Ermittlung des biologisch-immunreaktiven Verhältnisses von endogenem ACTH in equinen Blutproben. (The equine Cushing syndrome development of an ACTH-bioassay for determination of the biological- immunoreactive-ratio of endogenous ACTH in equine blood samples). Inaugural dissertation to obtain the degree of doctor of veterinary medicine (Dr. med. vet.). University of Veterinary Medicine Hannover.

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52. Towns, T.J., Stewart, A.J., Hackett, E., Zhong, Q., Munsterman, A., Wooldridge, A.A., Funk, R.A. and Hewes, C.A. (2010) Cortisol and ACTH concentrations in ill horses throughout 6 days of hospitalisation. J Vet Emerg Crit Care 20 (S1),

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53. van der Kolk, J.H., Heinrichs, M., van Amerongen, J.D., Stooker, R.C., in de Wal, L.J., van den Ingh, T.S. (2004) Evaluation of pituitary gland anatomy and histopathologic findings in clinically normal horses and horses and ponies with pituitary pars intermedia adenoma. Am J Vet Res. 65, 1701-7.

54. van der Kolk, J.H. Wensing, T., Kalsbeek, H.C. and Breukink, H.J. (1995) Laboratory diagnosis of equine pituitary pars intermedia adenoma. Domest. Anim. Endocrinol. 12, 35-39.

55. Walsh, D.M., McGowan, C.M., McGowan, T., Lamb, S.V., Schanbacher, B.J. and Place, N.J. (2009) Correlation of Plasma Insulin Concentration with Laminitis Score in a Field Study of Equine Cushing's Disease and Equine Metabolic Syndrome. J Equine Vet Sci 29, 87-94.

56. Wardlaw SL. 2011 Hypothalamic proopiomelanocortin processing and the regulation of energy balance. Eur J Pharmacol. 660(1):213-9.

57. Wilson, M.G., Nicholson, W.E., Holscher, M.A., Sherrell, B.J., Mount, C.D. and Orth, D.N. (1982) Proopiolipomelanocortin peptides in normal pituitary, pituitary tumor, and plasma of normal and Cushing's horse. Endocrinology. 110, 941-54

peptides in normal pituitary, pituitary tumor, and plasma of normal and Cushing's horse. Endocrinology. 110, 941-54

42

USEFUL LaBoRaToRy TESTS In HoRSES PREdISPoSEd To LaMInITIS

Andy Durham BSc.BVSc.CertEP.DEIM.DipECEIM.MRCVS,

The Liphook Equine Hospital, Forest Mere, Liphook, Hampshire, GU30 7JG, UK. andy@TheLEH.co.uk Tel 0044 1428 723594 Fax 0044 1428 722263

CLINICOPAthOLOgICAL fACtOrS IDENtIfIED IN EMS CASES

Equine Metabolic Syndrome (EMS) and pituitary pars intermedia dysfunction (PPID) represent the major endocrinopathic causes of laminitis in horses and the putative interrelationship between EMS and PPID is subject to much debate. It is evident that the distinction between the 2 conditions is not always clear-cut but they are regarded as separate entities with differing pathophysiology, treatment and management (Frank et al 2010). It is likely that the 2 conditions coexist in some animals and therefore a diagnosis of PPID cannot always be used to exclude one of EMS, but nevertheless an endocrine investigation of laminitis should always consider both conditions especially in horses in an older age group (e.g. > 10 years).

Study of EMS cases has revealed several measurable plasma analytes that serve as markers for the dysmetabolism that culminates in increased laminitis susceptibility and predominantly reflect dysregulation of glucose and lipid metabolism. Although the exact pathophysiologic pathways leading to laminitis have not been elucidated, it is likely that some of these analytes may have direct pathologic relevance whilst others simply act as indirect markers of abnormal metabolic responsiveness. Several measurable plasma analytes associated with EMS are described further below.

tests for dysregulation of glucose metabolism

A common feature of the various definitions of metabolic syndrome in humans is one or more indices of insulin resistance (IR) (Alberti et al 2009). Similarly IR has become a prominent component of EMS and consequent risk of laminitis (Frank et al 2010). Plasma glucose concentration is normally tightly regulated within physiological limits and arises primarily

al 2010). Plasma glucose concentration is normally tightly regulated within physiological limits and arises primarily 43

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from post-prandial enteric absorption and from hepatic gluconeogenesis during fasting. Hyperglycaemia is minimised primarily by increased insulin-dependent glucose uptake by insulin-sensitive tissues such as muscle and adipose tissue, and inhibition of on-going hepatic gluconeogenesis. It is apparent therefore that IR will destabilise the fine equilibrium between glucose and insulin concentrations which can then be exploited diagnostically.

Although many experimental studies aim to use specific and quantitative measures of IR such as the hyperinsulinaemic euglycaemic clamp or minimal model analysis of the frequently sampled intravenous glucose tolerance test, various simpler tests known or believed to correlate with insulin resistance or sensitivity are generally preferred in clinical practice (Wallace and Matthews 2002; Kronfeld et al 2005; Firshman and Valberg 2007) (table 2).

Hyperglycaemia, although relatively common in humans with metabolic syndrome, is relatively rare in EMS (Frank et al 2010) and PPID (Durham, unpublished) cases.

Perhaps the simplest useful test for dysregulation of glucose is measurement of insulin concentration. In addition to its simplicity, this test may be most pathogenically relevant given that it is likely to be hyperinsulinaemia rather than IR or hyperglycaemia that triggers laminitis (Asplin et al 2007; de Laat et al 2010, 2012).

Measurement of basal insulin concentrations is highly dependent upon recent carbohydrate ingestion and therefore, for standardisation, use of basal insulin concentration should ideally follow withholding of feed for about 6 hours (Frank et al 2010). However, fasting insulin concentrations may be normal in up to 70% of laminitis-prone subjects (AE Durham, unpublished data) indicating that fasting insulin is associated with a low sensitivity for prediction of laminitis risk in EMS and PPID.

As discussed above, an important defining feature of EMS is that certain individuals, and not others, are likely to suffer laminitis following pasture ingestion. Many important and interacting parameters may be influential in the mechanistic sequence of events occurring between grazing and laminitis. These might include a greater appetite for grass resulting in a larger amount of ingested NSC, improved assimilation of simple sugars from the ingested grass due to digestive and/or fermentative differences, a greater pancreatic insulinaemic response to the assimilated sugars and perhaps a heightened pathologic effect of insulin at cellular receptor and/or post-receptor level. In any event, it could be argued that the use of tests that most closely mimic at least some parts of this putative pathway may be most useful. Indeed, several studies have indicated that laminitis-prone individuals characteristically demonstrate an excessive hyperinsulinaemic response to grazing or orally adminstered carbohydrates (Bailey et al 2007, 2008; Tinworth et al 2011; Borer et al 2012), which may well represent a fundamental and crucial metabolic/endocrine difference between normal horses and those endocrinopathically predisposed to laminitis. In this respect the use of tests that examine the insulinaemic response to oral carbohydrate ingestion might appear even

this respect the use of tests that examine the insulinaemic response to oral carbohydrate ingestion might

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Useful laboratory tests in horses predisposed to laminitis

more attractive than more sophisticated tests examining responses to intravenous glucose and/or insulin. In the USA, the “oral sugar test” (OST) has proved popular (Frank 2011), whereas in the United Kingdom the “in-feed glucose test” is commonly used (tables 3 and 4). These two similar tests challenge the horse with corn syrup and glucose respectively and compare the insulinaemic response of the tested individual to that expected in a normal animal. It is assumed that an excessive insulinaemic response to the ingested carbohydrate represents a risk factor for laminitis. Comparison of 21 normal and 199 laminitis-prone individuals indeed revealed significantly greater insulin concentrations in the latter group at 2 hours following in-feed glucose (Figure 1).

Table 2. Practical tests used to estimate insulin resistance and sensitivity

tests commonly used to estimate insulin resistance

combined insulin glucose test (CGIT)

oral glucose tolerance test (OGTT)

oral sugar test (OST)

in-feed glucose test

basal insulin concentration (fasted and not fasted)

basal glucose concentration

insulin to glucose ratio

reverse inverse square of insulin (RISQI)

Table 3. Outline procedure of the oral sugar test (Frank 2011).

Oral Sugar test

Fast overnight (allow 1 flake of hay)

Dose with 15 mL Karo Light corn syrup per 100 kg BWT

Measure serum insulin at 60-90 minutes post dosing

Normal response < 60 mU/L insulin

Table 4. Outline procedure of the in-feed glucose test (AE Durham, unpublished data)

In-feed glucose test

Overnight fast

Give 0.5 or 1.0 g/kg BWT glucose or dextrose powder in a non-glycaemic feed (e.g. chaff)

Measure serum insulin and plasma glucose after 2 hours

Normal response:

0.5

g/kg dose: 2 hour insulin < 57 mU/L

1.0

g/kg dose: 2 hour insulin < 87 mU/L

Normal response: 0.5 g/kg dose: 2 hour insulin < 57 mU/L 1.0 g/kg dose: 2 hour

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XIV CONGRESO INTERNACIONAL DE MEDICINA Y CIRUGÍA EQUINA Figure 1. Serum insulin concentrations from 21 normal

Figure 1. Serum insulin concentrations from 21 normal and 199 laminitis-prone horses and ponies subject to the in-feed glucose test 2 hours following administration of 1.0 g/kg dextrose. Dotted line represents cutoff for normal response. Median (interquartile ranges) are 26.3 (10.4-51.1) and 333 (105-697) mU/L respectively (P<0.001). Using a cutoff of 81 mU/L, 78% of laminitis-prone individuals demonstrated hyperinsulinaemia.

tests for dysregulation of lipid metabolism

Both human and equine metabolic syndrome cases are also characterised by abnormal circulating lipids and lipid metabolites (Alberti et al 2009; Frank et al 2010). When non- esterified fatty acids (NEFAs) are released from adipose stores they are transported to the liver for re-esterification into triglyceride within very low density lipoprotein particles (VLDLs) that circulate in plasma to transport lipid to peripheral tissues for oxidation or for storage. High density lipoproteins also circulate and serve primarily to transport cholesterol. Insulin is a potent regulator of this pathway, preserving adipose stores and inhibiting VLDL synthesis, with the contrary effect of lipid mobilisation being facilitated in IR states (Large & Arner 1998; Bartels et al 2002; Kamagate et al 2008)

The only commonly assayed component of lipid transport and metabolism is plasma triglyceride concentration which largely represents plasma VLDLs. However, plasma free fatty acids are also relatively easily assayed. Obese, insulin resistant and laminitis-prone horses have been shown to have higher than normal plasma triglyceride concentrations, NEFAs, VLDL and HDL-cholesterol, the latter contrasting with findings in humans with metabolic syndrome (Frank et al 2006; Treiber et al 2006).

Adipokines

Adipocytes, macrophages and other cells composing adipose tissue synthesise and secrete a large and diverse family of proteins called adipokines that are important in the pathophysiology of conditions associated with obesity. Several adipokines have been

that are important in the pathophysiology of conditions associated with obesity. Several adipokines have been 46

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Useful laboratory tests in horses predisposed to laminitis

identified and studied in other species including leptin, adiponectin, resistin, visfatin, apelin, retinol binding protein as well as inflammatory cytokines probably released both by adipocytes and inflammatory cells within the fat such as TNF-alpha, IL-6, MCP1 (CCP-2) and IL-1 (Tilg and Moschen 2006).

Leptin is the best characterised adipokine and acts to suppress appetite centrally and improve insulin sensitivity peripherally (Konturek et al 2005). Obesity is associated with hyperleptinaemia and selective leptin resistance leading to inflammation and vascular dysregulation (Correia et al 2006; Guzik et al 2006). Several studies in horses have revealed leptin to be greater in obese, insulin resistant horses and also to be predictive of laminitis when > 7.3 ng/mL (Buff et al 2002; Cartmill et al 2003; Frank et al 2006; Kearns et al 2006; Carter et al 2009).

Adiponectin is a further adipokine peptide, found as a trimer, hexamer, or high molecular weight (HMW) multimer, the latter probably being most biologically active (Wang et al 2008). Compared to other adipokines, adiponectin appears to have protective metabolic, vascular and anti-inflammatory effects and it is decreased in obesity and IR in horses (Cnop et al 2003; Kearns et al 2006; Gordon et al 2007).

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tEStS fOr PPID

It is not yet clear why PPID is associated with increased risk of laminitis. As hypercortisolaemia is not associated with PPID this seems an unlikely mechanism despite frequent comment to the contrary. PPID cases are known to be frequently insulin resistant and hyperinsulinaemic and thus the cause of PPID-associated laminitis may be no different to other causes of endocrinopathic laminitis. Indeed it has been shown that PPID cases are likely to respond to oral glucose with an excessive hyperinsulinaemia in a similar fashion to EMS cases. Why PPID cases tend to develop hyperinsulinaemia is unknown but may relate either to insulin resistance or to a direct stimulatory effect on the pancreas by pars intermedia peptides such as beta cell tropin.

Laboratory testing of PPID cases

In general there are 2 main reasons to perform laboratory testing of suspected PPID cases. Firstly, for confirmation of pars intermedia dysfunction and, secondly, to provide insight into the wider health status of the individual. Routine haematology and biochemistry is not useful in establishing a diagnosis of PPID although a general health screen and faecal worm egg count may form a useful adjunctive part of PPID investigation by identification of concurrent disease. Measurement of serum insulin and plasma glucose are also recommended (see above).

The presence of advancing age and clinical signs may often be considered adequate for a clinical diagnosis in the field. However, laboratory testing is also of importance for several reasons including investigation of equivocal cases, for differentiation from Equine Metabolic Syndrome (NB both conditions might coexist), for owners reluctant to start life- long treatment without strong evidence as well as for monitoring of treatment efficacy.

Current diagnostic tests that are considered to possess adequate accuracy and availability for clinical use comprise basal plasma ACTH concentration, the overnight dexamethasone suppression test (ODST) and the TRH stimulation test (measuring ACTH).

Basal Plasma ACth Concentration

[Conversion factor for ACTH: pg/mL B pmol/L (x 0.2202); pmol/L B pg/mL (x 4.541)]

In normal horses physiologic production of ACTH occurs in corticotrope cells in the pars distalis which release the hormone in response to corticotropin releasing factor (CRF) following cleavage from the parent peptide POMC. It is thought that in normal horses only about 2% of circulating ACTH is derived from the melanotrope cells of the pars intermedia as further cleavage normally results in conversion of ACTH into alpha-MSH and CLIP (Wilson et al. 1982). In PPID cases there is overproduction of immunoraective ACTH from pars intermedia melanotropes into the plasma (Orth and Nicholson 1982, Wilson et al. 1982).

immunoraective ACTH from pars intermedia melanotropes into the plasma (Orth and Nicholson 1982, Wilson et al.

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Measurement of basal plasma ACTH is by far the most popular diagnostic test for PPID, perhaps due to the relative simplicity of collection of a single sample and also the availability of seasonal reference ranges in some laboratories that allow testing at any time of year (Copas and Durham 2012). Although increased basal plasma ACTH concentration is clearly associated with the presence of PPID (van der Kolk et al. 1995), secondary adrenal hyperplasia is frequently absent and plasma cortisol concentration is generally normal (Beech et al. 2011a, McFarlane et al. 2006). This is most likely as a result of the pars intermedia-derived immunoreactive ACTH in PPID cases being significantly less bioactive than the pars distalis-derived ACTH from normal horses (Orth and Nicholson 1982, Sommer 2003; Beech et al. 2011a, Cordero et al. 2011).

Careful sample processing is vital for reliable interpretation of plasma ACTH owing to several in vivo and in vitro factors other than PPID that could influence the measured concentration. Variation in results from different analysers, at different times of year and in different geographic locations makes it important that individual laboratories establish reference intervals (Bradaric et al. 2012; Schott et al. 2012). Further potentially important considerations are discussed below:

Seasonality

Donaldson et al. (2005) first noted that ACTH concentration in healthy horses and ponies was significantly higher when measured in September compared with January and May, indicative of an autumnal increase in pituitary activity and ACTH secretion, and advised to avoid testing for PPID at that time of year. This circannual variability has been confirmed by several other studies some of which established seasonal reference intervals thus enabling year-round use of ACTH as a diagnostic test (Copas and Durham 2012; Gimplinger and Fey 2012). Copas and Durham (2012) further showed that the autumnal (August, September and October) increase in plasma ACTH was even greater in horses with PPID than in normal horses indicating that responses to seasonal cues are retained in PPID (Figure 1). Consistent with this, a more recent study demonstrated that the highest sensitivity and specificity of basal plasma ACTH for PPID diagnosis was in the autumn using a seasonally adjusted reference range (McGowan et al. 2013b).

plasma ACTH for PPID diagnosis was in the autumn using a seasonally adjusted reference range (McGowan

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Useful laboratory tests in horses predisposed to laminitis

Useful laboratory tests in horses predisposed to laminitis Figure 1. Illustration of seasonal variability of median

Figure 1. Illustration of seasonal variability of median plasma ACTH in normal (n=156, black bars) and PPID horses (n=962, grey bars) (data from Copas and Durham 2012).

In vitro stability of ACTH

ACTH is subject to further in vitro degradation such that immunoreactivity decreases over time following sampling. Perkins and colleagues (2002) showed no significant decrease in measured ACTH when plasma was kept chilled for 8 hours. Durham and Copas (2011) showed that when plasma was stored at 20-40°C there was a progressive decrease in measured ACTH but this was not significant until between 3 to 6 hours after storage, leading to advice that samples should be chilled within 3 hours of collection and maintained in a chilled state until testing.

Protease inhibitors such as aprotinin and N-phenylmaleimide have been reported in non-equid species as an attempted means to increase stability of ACTH in vitro. Several equine studies have found that such products fail to prevent ACTH degradation and therefore they are not recommended (Bruns 2001; Durham and Copas 2011; Rendle et al. 2012b).

Studies of delayed centrifugation of samples have indicated that unseparated whole blood or gravity separated plasma are suitable for testing as long as the samples are chilled promptly after collection and centrifuged upon receipt by the laboratory (Durham and Copas 2011). However, should a non-centrifuged or gravity separated sample become frozen then spuriously high ACTH concentrations will be measured, possibly as a result of cellular remnants carrying immunoreactive peptides (Durham and Copas 2011).

will be measured, possibly as a result of cellular remnants carrying immunoreactive peptides (Durham and Copas

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Timing of sampling

A few studies have looked into the possibility of diurnal variability in ACTH secretion and have generally found that although some variability exists, it is not prominent and unlikely to affect diagnosis (Lee at al. 2010, Cordero et al. 2012, Rendle et al. 2012a). However, ACTH concentrations may vary slightly through the day and therefore standardisation of sampling times is preferable when further samples are taken for comparison during monitoring.

Further possible short term variability in ACTH secretion may occur as a result of pulsatile secretion in a small minority of cases although a single sample will generally be diagnostically acceptable. One study has also indicated that plasma ACTH concentrations are significantly higher when measured 2 hours after feeding than after a 12 hour fast suggesting that diet may also need to be standardised when using this test for PPID investigation (Diez de Castro et al 2013).

Stress/pain

ACTH may intuitively be susceptible to variability as a result of the pain of laminitis, stress of transport or even any aversion to the blood sampling procedure. Several studies have examined this possible effect and concluded that pain, stress and concurrent illness are only likely to affect diagnostic usefulness of ACTH when severe (Alexander et al. 1988; Couetil et al. 1996). General anaesthesia, strenuous exercise, moderate to severe illness and severe pain may all increase plasma ACTH (Taylor et al. 1989; Alexander et al. 1991; Towns et al. 2010). Where these conditions exist care should be taken in interpreting the result.

The above findings are condensed into general advice when using ACTH as a diagnostic aid for PPID (table 2).

Table 2. Advice for pre-test handling of sample collected for ACTH analysis

1. Collet EDTA plasma sample at any time of day ( but be consistent in re-testing for comparision later)

2. Chill sample within 3 hours of collection

3. Centrifuge prior to shipping to laboratory (gravity separated samples can be shipped as long as they remain chilled and do not freeze)

4. Ship to laboratory using guaranteed overnight delivery in chilled packaging (freeze centrifuged plasma if delivery is delayed)

The diagnostic accuracy of plasma ACTH for investigation of suspected PPID cases has been subject to several studies. Van der Kolk et al. (1995) found perfect discrimination between 24 post-mortem confirmed pituitary adenoma and 7 normal horses using a basal ACTH cutoff of 55 pg/mL (12.1 pmol/L) using radioimmunoassay. Another series

adenoma and 7 normal horses using a basal ACTH cutoff of 55 pg/mL (12.1 pmol/L) using

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Useful laboratory tests in horses predisposed to laminitis

of publications, using chemiluminescent assay, comparing 13 post-mortem confirmed clinical PPID cases versus 22 normal horses indicated sensitivity for basal ACTH of 77% and specificity of 100% using a cut-off of 35 pg/mL (7.7 pmol/L), although test sensi- tivity was <50% when subclinical and mild clinical PPID cases were included (Beech et al. 2007, 2011a,b, pers comm). One study has looked at the sensitivity and specificity of basal ACTH using seasonally adjusted reference ranges for diagnosis of clinical PPID cases (McGowan et al 2013b). In that study, the sensitivity and specificity were 80% and 82% respectively during the non-autumn months, and 100% and 95% in the autumn when seasonally adjusted reference ranges were used. Thus it may be uncommon for horses with normal pituitary glands to have increased basal ACTH concentration. However, some PPID cases may not demonstrate increased ACTH.

OVErNIght DEXAMEthASONE SUPPrESSION tESt (ODSt)

[Conversion factor for cortisol: ng/mL B nmol/L (x 2.759); nmol/L B ng/mL (x 0.362)]

In contrast to pars intermedia melanotropes, pars distalis corticotropes are subject to negative feedback from endogenous cortisol and administration of exogenous glucocorticoids leading to supressed ACTH secretion. Thus in the normal horse, where ACTH comes almost exclusively from the pars distalis, exogenous glucocorticoids are followed by a significant decrease in plasma cortisol concentration. However, in PPID where significant quantities of ACTH are produced by the pars intermedia, cortisol secretion may be maintained in the face of administration of glucocorticoids (Dybdal et al. 1994).

The ODST might be favoured in some areas due to possibly more widespread availability of cortisol assays and also the greater in vitro stability of cortisol versus ACTH. Performance of the ODST requires veterinary attendance on 2 consecutive days presenting cost and time implications. Concerns also exist regarding possible adverse effects of dexamethasone administration in laminitis-prone individuals. Furthermore, ODST is subject to seasonal effects with false positive results likely in the autumn meaning that the test should not be used then (Donaldson et al. 2005; Schott et al. 2007). The procedure for the ODST is outlined in table 3.

Table 3. Protocol for performance of the overnight dexamethasone suppression test.

1. Collet baseline serum or plasma (consult receiving laboratory) sample for cortisol (this sample can be omitted to reduce costs)

2. Inject 0.04 mg/kg BW dexamethasone iv or im

3. Collect further sample for cortisol between 18-20 hours later

4. Centrifuge prior to shippng to laboratiry

iv or im 3. Collect further sample for cortisol between 18-20 hours later 4. Centrifuge prior

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High cortisol concentrations 18-20 hours following dexamethasone are indicative of PPID. Combination of 3 published studies (n=111) comparing clinical PPID cases with normal horses, including post-mortem confirmation of diagnosis and a cut-off of 27 nmol/L (1 mg/dL), indicated an overall test sensitivity of 89% and specificity of 88% (Dybdal et al. 1994; Beech et al. 2007; Frank et al. 2006). As with basal ACTH testing, ODST is likely to be less sensitive in subclinical or mild clinical PPID cases.

trh StIMULAtION tESt

Concerns of low sensitivity of basal ACTH and ODST for identification of PPID has provoked investigation of stimulation tests as a means of detecting PPID cases, especially those that might be in an early clinical or even pre-clinical phase. TRH receptors exist on many cells within the central nervous system and pituitary gland. McFarlane et al. (2006) confirmed the presence of mRNA for TRH Type 1 receptors in both pars intermedia melanotropes and pars distalis corticotropes in normal and PPID horses. Administration of TRH in vivo leads to increases in plasma concentrations of ACTH and a-MSH in normal and PPID horses, although the stimulatory effect is greater in PPID cases (McFarlane et al. 2006, Beech et al. 2007, 2011a,b). Plasma ACTH is seen to peak within 2-10 minutes of TRH injection and then gradually decreases back towards baseline by about an hour (Beech et al. 2007, 2011a,b; Funk et al. 2011) (figure 2).

(Beech et al. 2007, 2011a,b; Funk et al. 2011) (figure 2). Figure 2. Median plasma ACTH

Figure 2. Median plasma ACTH response to 1mg TRH iv in 44 horses with pituitary hyperplasia (PH+) and 22 horses with normal pituitary glands (PH-). PH+ and PH- significantly differ at all time points except 2 and 180 mins (Mann Whitney Test p<0.02) (data from Beech et al. 2007, 2011, pers comm J Beech) (NB not all data exists for every horse at every time point).

(data from Beech et al. 2007, 2011, pers comm J Beech) (NB not all data exists

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Useful laboratory tests in horses predisposed to laminitis

TRH is not licensed for use in horses and owners should be warned that reactions to intravenous administration including transient muscle trembling, yawning, lip-smacking, flehmen and coughing are not uncommon (Beech et al. 2007). Supplies of TRH may be limited and costly in some areas creating further problems with performing this test. The response to TRH is greater in the autumn months than at other times of year (Beech et al. 2007, 2011a,b; Funk et al. 2011) and, as no seasonal reference intervals are yet published, the test cannot be properly interpreted at that time of year. The recommended procedure for TRH stimulation testing is outlined in table 4.

Table 4. Procedure for TRH stimulation testing

1. Collect baseline EDTA plasma sample for ACTH analysis

2. Inject 1 mg TRH iv

3. Collect a further EDTA plasma sample at 10 minutes following TRH

4. Process plasma samples as per measurement of basal plasma ACTH procedure above

Currently the TRH stimulation test appears to offer higher diagnostic sensitivity compared with other tests for PPID (Beech et al. 2007, 2011a,b) and possibly offers the prospect of diagnosis at an earlier stage of disease. For diagnostic purposes, measuring plasma ACTH at 10 minutes post-TRH is recommended using a cutoff of 110 pg/mL, although the reference value might well be amended as greater numbers of tests are performed.

Additional valuable tests

The causal mechanism linking PPID with laminitis is unknown. Hyperinsulinaemia is well established as one of only a few proven causes of laminitis in horses and ponies (Asplin et al. 2007, de Laat et al. 2010) and insulin sensitivity is commonly decreased in association with PPID (Klinkhamer et al. 2012). Furthermore, McGowan et al. (2004) found that basal insulin concentration was negatively associated with prognosis in PPID cases and Walsh and colleagues (2009) also found associations between laminitis and insulin concentration in PPID cases.

Hence, the measurement of serum insulin and glucose is strongly recommended in PPID cases as an indicator of laminitis risk, diabetes mellitus and prognosis. However, the conditions under which the test is performed have a large influence on prevalence of abnormal results. Fasting hyperinsulinaemia is uncommon in PPID cases although the majority demonstrate an excessive insulinaemic response to glucose ingestion and therefore insulin response to oral sugar challenge is more sensitive than basal insulin concentrations (Table 5).

and therefore insulin response to oral sugar challenge is more sensitive than basal insulin concentrations (Table

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Table 5. Prevalence of hyperinsulinaemia in PPID cases according to test conditions (AE Durham unpublished data).

total PPID cases

Number

hyperinsulinaemic

%

hyperinsulinaemic

Fasting hyperinsulinaemia (>20 mU/L)

 

11

1

9%

Non-fasting hyperinsulinaemia (>50 mU/L)

1145

339

30%

 

88

60

68%

Hyperinsulinaemia @ 2hrs after 1 g/kg glucose (>81 mU/L)

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49. Schott, H.C., Eberhart, S.W., Nachreiner, R.F. and Beyerlein, S. (2007) Effect of season on overnight dexamethasone suppression test results in aged horses without clinical signs of pituitary pars intermedia dysfunction (abstr). Veterinary Dermatology 18, 193.

50. Schott, H.C., Schenck, P. and Refsal, K. (2012) Comparison of assay kits for measurement of plasma adrenocorticotropin concentration. Abstract Equine Endocrinology Summit, Boston.

51. Sommer K. (2003) Das Equine Cushing-Syndrom: Entwicklung eines ACTH- Bioassays für die Ermittlung des biologisch-immunreaktiven Verhältnisses von endogenem ACTH in equinen Blutproben. (The equine Cushing syndrome development of an ACTH-bioassay for determination of the biological- immunoreactive-ratio of endogenous ACTH in equine blood samples). Inaugural dissertation to obtain the degree of doctor of veterinary medicine (Dr. med. vet.). University of Veterinary Medicine Hannover.

52. Taylor, P.M. (1989) Equine stress responses to anaesthesia. Br J Anaesth. 63, 702-

9.

53. Towns, T.J., Stewart, A.J., Hackett, E., Zhong, Q., Munsterman, A., Wooldridge, A.A., Funk, R.A. and Hewes, C.A. (2010) Cortisol and ACTH concentrations in ill horses throughout 6 days of hospitalisation. J Vet Emerg Crit Care 20 (S1),

A16-17.

54. van der Kolk, J.H., Heinrichs, M., van Amerongen, J.D., Stooker, R.C., in de Wal, L.J., van den Ingh, T.S. (2004) Evaluation of pituitary gland anatomy and histopathologic findings in clinically normal horses and horses and ponies with pituitary pars intermedia adenoma. Am J Vet Res. 65, 1701-7.

55. van der Kolk, J.H. Wensing, T., Kalsbeek, H.C. and Breukink, H.J. (1995) Laboratory diagnosis of equine pituitary pars intermedia adenoma. Domest. Anim. Endocrinol. 12, 35-39.

56. Walsh, D.M., McGowan, C.M., McGowan, T., Lamb, S.V., Schanbacher, B.J. and Place, N.J. (2009) Correlation of Plasma Insulin Concentration with Laminitis Score in a Field Study of Equine Cushing's Disease and Equine Metabolic Syndrome. J Equine Vet Sci 29, 87-94.

57. Wilson, M.G., Nicholson, W.E., Holscher, M.A., Sherrell, B.J., Mount, C.D. and Orth, D.N. (1982) Proopiolipomelanocortin peptides in normal pituitary, pituitary tumor, and plasma of normal and Cushing's horse. Endocrinology. 110, 941-54

peptides in normal pituitary, pituitary tumor, and plasma of normal and Cushing's horse. Endocrinology. 110, 941-54

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DIEtAry CONtrOL Of OBESIty AND LAMINItIS rISk

Andy E Durham

BSc . BVSc . CertEP . dEIM . dipECEIM . MRCVS . RCVS & European Specialist in Equine Medicine, The Liphook Equine Hospital, Hampshire, GU30 7JG

Recent equine health surveys indicate that around 50% of horses and ponies in the UK are overweight. To make matters worse the same surveys tend to suggest that many owners do not even recognise that their animals are overweight (Wyse et al 2008, Stephenson et al 2011). Experience indicates that even those owners that do recognise that their horses have a problem with obesity tend to become tolerant of the problem and adopt the defeatist attitude that certain “good doing” types will inevitably be overweight and there is little that can be done to avoid or correct this. This concerning habituation and acceptance of obesity can even progress to the tolerance of the health consequences of obesity. Owners of ponies may comment that “he always tends to be a bit lame in the spring” implying that clinical laminitis is normal and to be expected!? An acceptance and resigned attitude to the occurrence of laminitis, the second biggest killer of equines in the UK, cannot be a satisfactory situation.

Equine metabolic syndrome (EMS) is a relatively recent concept that has helped us all to focus on the underlying causes of laminitis. Henry Ford, the founder of the Ford Motor Company, said "If you always do what you've always done, you'll always get what you've always got". This statement bears much relevance to many diseases seen in equine practice (none more so than laminitis) and is worth repeating to the owner of a laminitis case who worries whether or not the laminitis is likely to recur. Clearly recurrence of laminitis is to be expected if the causal factors are not dealt with effectively! Obesity, either generalised or regional, ranks very high in the list of causal factors deserving of correction and is a strong driving force for insulin resistance and hyperinsulinaemia and a fundamental component of EMS. Breeds commonly afflicted by EMS and laminitis are generally metabolically very efficient and weight loss is notoriously difficult to achieve. However, it is important to realise that weight loss can be achieved in such individuals although strict discipline and dietary restriction will be required. Recent studies have enlightened us to the degree to which the ration must be limited in order to succeed (see below). Success will not be easy, but it is an important first step to accept that it is possible!

to succeed (see below). Success will not be easy, but it is an important first step

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Dietary control of the processes of EMS and increased laminitis risk is important in two broad fashions

1. Excessive adiposity can only be controlled by creating a relative dietary calorie deficit whereby energy expenditure exceeds intake. There is clear evidence that weight gain is associated with increased insulin resistance in horses with consequent adverse health effects (Carter et al 2009).

2. Restriction of dietary non-structural carbohydrates (NSC: simple sugars, starches and fructans) limits post-prandial hyperinsulinaemia which is recognised as a key trigger factor for laminitis (Asplin et al 2007). Dietary sugars and starches are likely to derive from concentrate feeds whereas grazing supplies primarily fructans and simple sugars.

Dietary restriction should always be approached with some caution and is deserving of veterinary supervision due to a few areas of concern.

1. There is a possible risk of triggering clinical hyperlipaemia in an obese, insulin resistant, probably sedentary individual who will be subject to severe calorie restriction.

2. By deliberately implementing a calorie-restricted ration, there may be a consequent and inadvertent creation of a protein and micronutrient deficiency in the diet with possible negative impact on many metabolic processes including healthy hoof growth.

3. Dietary restriction and feeding a more highly lignified diet may be associated with possible adverse effects on gastrointestinal health including gastric ulceration and impaction colic.

4. By restricting the diet of obese individuals it is likely that the time spent exhibiting ingestive behaviours will also be limited will possible adverse effects on behaviour and stereotypies.

Dugdale and co-workers (2010) demonstrated the issue of protein deficiency to be real in a study of severe dietary restriction in Welsh ponies although failed to find any evidence of hyperlipaemia risk. Although somewhat reassuring it is worth remembering that most clinical hyperlipaemia cases are seen in donkeys and Shetland ponies and these breeds might react differently to dieting than welsh ponies. Another study showed no concerns of gastric ulceration through a long period of dietary restriction and weight loss in Shetland ponies (Bruynsteen et al 2012).

ulceration through a long period of dietary restriction and weight loss in Shetland ponies (Bruynsteen et

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Dietary control of obesity and laminitis risk

Thus dietary control for EMS and laminitis may be summarised by the restriction of both dietary calories and NSC, whilst ensuring continued provision of other dietary components such as proteins and micronutrients, and should perhaps be implemented gradually especially in hyperlipaemia-susceptible breeds. Efforts should be made to extend the feeding period as long as possible by using narrow-weave, double or triple haynets, centrally hanging rather than wall-hanging hay nets, etc…

Although it is hard to predict body fat content in an obese individual, it is likely that most obese horses and ponies have a body fat percentage between 15 and 30% (Dugdale et al 2012) and a reasonable target for weight loss will often be in the region of 10-20% initial body mass. This can be achieved at a rate of 0.5-1.0% body mass per week although weight loss may be greater in the first week of dietary restriction due to decrease in “gut-fill”. Generally, monitoring weight loss the first week of dietary restriction should be ignored as it will relate primarily to gut-fill rather than loss of true body (fat) mass. Duration of the weight loss programme clearly depends on the degree of initial adiposity but is likely to extend over between 2-6 months if properly applied.

Caloric requirements of individual obese animals cannot be predicted with any reasonable degree of accuracy due largely to inter-individual variability and the recently demonstrated spectrum of “weight-loss-sensitive” and “weight-loss-resistant” individuals which is not entirely breed dependent (Argo et al 2012). Furthermore it is unusual to be able to accurately calculate the exact digestible energy and more detailed nutrient analysis of an entire equine ration in practice. Thus an estimate of total required intake must inevitably be made and then followed by a monitoring protocol so that further changes and adjustments to the diet can be made as required.

Monitoring should ideally be on a weighbridge although evidence suggests that morphometric measurements such as girth circumference, rump-width or ultrasonic fat depth may serve as more easily accessible alternatives (Dugdale et al 2010). Availability of readily portable weighbridges does make “weighing clinics” a reality in modern equine ambulatory practice however. Clinicopathologic variables such as fasting insulin, insulin response to in-feed glucose, the combined insulin glucose test, the insulin tolerance test and plasma leptin concentration might also be usefully employed as objective markers of success.

Undoubtedly the most effective general means of achieving weight loss is when the carer has total control of exactly what and how much the horse or pony is eating. This is impossible when grazing is allowed, even for short periods and even with a grazing muzzle. Ponies are notorious in their ability to rapidly consume surprisingly large quantities of grass. Most ponies can probably consume their total daily energy requirements in as little as 3 hours of pasture turnout! (Dr PA Harris, personal communication). Thus, even restricted grazing should ideally not be permissible during a weight loss programme, although may be reintroduced carefully, perhaps with a grazing muzzle, when weight loss has been achieved. Evidence suggest that grazing muzzles typically reduce grass intake to about 20% of that when a muzzle is not worn. Turnout in a sand school or in a fenced-off area that has been treated with herbicide or covered in wood chips allows

Turnout in a sand school or in a fenced-off area that has been treated with herbicide

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some exercise, clean air and mental stimulation whilst maintaining full dietary control. Everything that the horse or pony eats should first be weighed and be of acceptable dietary quality, especially with respect to energy and NSC content. Combining dietary control with increased exercise should be encouraged where lameness allows.

A diet with restricted calories, low NSC, high fibre and adequate protein and micronutrients is required. At its simplest, the diet must comprise 2 components:

1. The staple of the diet will be preserved forage, preferably hay. In native ponies and donkeys then a small amount of straw might be mixed with the hay although this should be done gradually and carefully to minimise the risk of impaction colic. Forage should be weighed dry and then soaked for at least an hour in warm water before feeding in order to remove some of the water soluble carbohydrates (WSC: simple sugars and fructans) from the forage and therefore reduce the glycaemic and insulinaemic effects of the diet.

2. Providing an additional supplementary feed in addition to forage has the dual advantage of providing a vehicle for delivery of oral drugs and also allows balancing of the diet with respect to protein and micronutrients. Such additional feed can be formulated from several commercial sources by estimating protein and micronutrient requirements and mixing appropriate amounts of chaff-based feeds and fedd-balancers (NB. proprietary label recommendations are not necessarily appropriate during dietary restriction programmes). Achievement of NRC requirements with respect to protein and micronutrients is essential.

Evidence from recent studies suggests that in order to achieve weight loss in good- doing types within a reasonable time-frame, total daily dry matter intake will need to be restricted to between 1.0 and 1.5% bodyweight daily (approximately 1.2-1.7% weighed “as fed”). This typically represents approximately one half of voluntary feed intake and therefore represents, necessarily, quite a harsh diet.

There is no doubt that obesity in horses and ponies is a current and serious threat to equine health. Far more horses in the UK suffer morbidity and mortality from overfeeding than from underfeeding yet most horse owners appear happy to ignore this obvious link between diet and health, in marked contrast to the public reaction when underfed horses are observed. It seems that there has been a general acceptance and tolerance of obesity and even its health consequences such as laminitis which is an appalling state of affairs for such a painful and life-threatening, yet controllable and preventable problem. Compliance remains the greatest obstacle to a successful weight loss programme. Appropriate dietary management is an absolute prerequisite for reversal of obesity and control of laminitis risk. The dietary principles on which a weight loss programme is based are by no means complex but weight loss requires veterinary supervision in order to be achieved safely and effectively. Greater veterinary interest and involvement in the implementation and monitoring of weight loss programmes is hopefully are area that will evolve and expand within our profession in coming years.

of weight loss programmes is hopefully are area that will evolve and expand within our profession

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rEfErENCES

1. Asplin KE, Sillence MN, Pollitt CC, McGowan CM. 2007 Induction of laminitis by prolonged hyperinsulinaemia in clinically normal ponies. Vet J.174(3):530-5.

2. Argo CM, Curtis GC, Grove-White D, Dugdale AH, Barfoot CF, Harris PA. 2012 Weight loss resistance: A further consideration for the nutritional management of obese Equidae. Vet J. 194(2):179-88.

3. Bruynsteen L, Vandevelde K,, Harris PA, Janssens GPJ, Hesta M. 2012 The effect of different levels of energy restriction on physical, metabolic, morphometric and animal welfare parameters. Proc. EVCVN Congress 16: 87.

4. Dugdale AH, Curtis GC, Cripps P, Harris PA, Argo CM. 2010 Effect of dietary restriction on body condition, composition and welfare of overweight and obese pony mares. Equine Vet J. 42(7):600-10

5. Dugdale AH, Grove-White D, Curtis GC, Harris PA, Argo CM. 2012 Body condition scoring as a predictor of body fat in horses and ponies. Vet J. 194(2):173-8.

6. Stephenson HM, Green MJ, Freeman SL. 2011Prevalence of obesity in a population of horses in the UK.Vet Rec. 168(5):131.

7. Wyse CA, McNie KA, Tannahill VJ, Murray JK, Love S 2008 Prevalence of obesity in riding horses in Scotland.Vet Rec.162(18):590-1.

KA, Tannahill VJ, Murray JK, Love S 2008 Prevalence of obesity in riding horses in Scotland.Vet

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trEAtMENt AND MONItOrINg Of hOrSES wIth PItUItAry PArS INtErMEDIA DySfUNCtION

Andy E Durham

BSc . BVSc . CertEP . dEIM . dipECEIM . MRCVS . RCVS & European Specialist in Equine Medicine, The Liphook Equine Hospital, Hampshire, GU30 7JG

The treatment of choice for PPID is pergolide mesylate (Prascend, Boehringer Ingelheim) which is licensed for use in horses. Use of other unlicensed drugs such as bromocryptine and cyproheptadine is reported although less supportive evidence exists (Beck 1992, Perkins et al 2002). As PPID is a highly heterogeneous disease varying from none/mild signs to overt and obvious clinical signs and from pars intermedia hyperplasia to microadenoma to macroadenoma (Heinrichs et al. 1990, van der Kolk et al. 2004, Miller et al. 2008), it follows that required doses for control of PPID may vary between cases, in addition to possible inter-individual variation in bioavailability.

Treatment efficacy can be evaluated empirically after 1 to 3 months on the basis of clinical response including start of hair shedding, improvement of laminitis and general attitude, increasing activity and a decrease in water consumption if previously polydipsic (Pongratz et al. 2010; Rohrbach et al. 2012). However, monitoring changes in laboratory indicators of PPID may offer a more objective and more sensitive means of monitoring response to treatment. Several small studies have documented improvement in laboratory variables including basal ACTH and overnight dexamethasone suppression test (ODST) response as objective markers of efficacy following treatment with pergolide or cyproheptadine (Peters et al. 1995; Schott et al. 2001, Donaldson et al. 2002, Perkins et al. 2002, Rohrbach et al. 2012). In one large study of 113 PPID cases following treatment with pergolide for 180 days, improvement in clinical signs and blood test results (basal ACTH or ODST) was observed in 76% of cases (Andrews et al. 2011). A recent study of laboratory samples from over 2000 PPID cases indicated that 55% of pergolide treated PPID cases showed a greater than 75% decrease in baseline ACTH and/or return to reference interval within 4 months of starting treatment, typically at 0.002 mg/kg (Rendle et al. 2013b).

return to reference interval within 4 months of starting treatment, typically at 0.002 mg/kg (Rendle et

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Although consensus appears to favour a starting dose of pergolide of approximately 0.002 mg/kg BW once daily in general practice, the expected timing of detectable response to treatment has not been well defined. A measurable response to pergolide treatment can often happen within hours of starting treatment. Durham et al (2009) described a case of type 2 diabetes mellitus secondary to PPID where a persistent hyperglycaemia (15 mmol/L) was seen to normalize to approximately 5 mmol/L within 12 hours of the first dose of pergolide. Further data has also indicated that many horses show a significant decrease in plasma ACTH within 2-12 hours of starting pergolide treatment (Rendle, unpublished) although progressive further decreases can occur thereafter. In one study that followed 33 PPID horses that responded well to pergolide therapy, only 1 (3%) had not responded by 28 days but did so later (Durham and Copas 2012). Thus it is recommended that laboratory tests are rechecked approximately 4 weeks following initiation of pergolide therapy or following dosage increases. If a good response (Lower basal ACTH; normal ODST response; normalization of hyperglycaemia) is going to occur then it is likely to do so by 4 weeks in the majority of cases. However, treatment response can occasionally be delayed far longer than this perhaps reflecting more established and resistant pars intermedia pathology. Some PPID cases that initially fail to respond to pergolide treatment may eventually respond (as judged by clinical and laboratory tests) after as long as 3 to 4 years’ treatment (HC Schott, unpublished data).

Currently, for best practice it is recommended that the following general protocol is used for management of PPID cases:

1. Obtain baseline clinical and endocrine values e.g. basal plasma ACTH, basal glucose and insulin, and document clinical findings.

2. Owners should be encouraged to monitor appetite, hair coat, water intake and bed wetting when housed, body condition score including estimation of muscle loss as well as fat score, laminitis/lameness and general demeanor monthly.

3. Calculate the starting dose of pergolide based on approximately 0.002 mg/kg BW PO q24h (to the nearest 0.5 mg total dose) (table 1).

Table 1. Suggested starting dosage of pergolide for treatment of PPID by bodyweight

Body weight

Starting Daily Dose

200-350 kg

0.5 mg

350-600 kg

1.0 mg

601-850 kg

1.5 mg

4. After one month of treatment, re-evaluate baseline clinical and endocrine values as well as owner-reported improvements. One or more clinical signs is expected to improve and/or the basal ACTH to have returned to normal or close to normal range for that time of year.

is expected to improve and/or the basal ACTH to have returned to normal or close to

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5. If clinical and/or endocrine improvements are not noted, increase the dose of pergolide by 0.001 mg/kg BW.

6. Re-evaluate monthly with increases in the pergolide dose by 0.001 mg/kg BW until clinical signs and endocrine variables have improved or a maximal dose of 0.010 mg/kg BW has been reached.

7. If signs of inappetance or depression are observed, reduce the dose by increments of 0.001 mg/kg BW and investigate for concurrent disease.

8. Once the signs have been successfully controlled, clinical and endocrine monitoring can reduce to 2-4 times per year, with at least one of these scheduled for between August and October (when test sensitivity and specificity are highest).

9. Owners should continue to monitor at least monthly and alert their veterinarian if there is deterioration or development of any new clinical signs.

10. If clinical signs and endocrine test results are well controlled for > 3 months, a slow reduction in the dose by 0.001 mg/kg BW per month can be attempted, with a minimal dose not less than 0.002 mg/kg BW. Doses less than 0.002 mg/ kg BW may result in treatment failure and reductions below this dose rate should be monitored carefully.

POSSIBLE DILEMMAS ArISINg DUrINg PPID MANAgEMENt

results from basal ACth or ODSt are in the “grey-zone”

Few clinical or laboratory tests produce entirely clear and dichotomous positive or negative results and it should be expected that in PPID investigation, as with most other medical investigations, some results will create interpretative difficulties. Interestingly original description of basal ACTH (van der Kolk 1995) and ODST (Dybdal et al. 1994) for diagnosis of PPID indicated 100% sensitivity and specificity although it was likely that normal horses were compared with those with advanced clinical disease in those early studies. Discordance between results of different tests for PPID is well recognized in cases with milder pituitary changes. In one study 21.5% PPID cases had different qualitative test results when tested with ODST and basal ACTH (McFarlane et al. 2012). Intuitively, early and/or mild clinical disease is likely to produce endocrine test results closer to the laboratory reference interval cut-off and so further testing (e.g. TRH stimulation test) should be considered under such circumstances.

Consideration of potential confounding factors for the test performed (e.g. stress, pain, sedation, in vitro chilling, etc…) is important to improve test specificity. If no confounding is suspected then retesting using the same test in 3 – 6 months might allow for some disease progression improving test sensitivity. Re-testing basal ACTH between August and October using seasonally adjusted reference intervals is associated with

Re-testing basal ACTH between August and October using seasonally adjusted reference intervals is associated with 73

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higher test sensitivity than testing at other times of year and increases the likelihood of detecting PPID (Copas and Durham 2012; McGowan et al. 2013). Another option is

to re-test using a different test and the TRH stimulation test is worthy of consideration for this purpose as its sensitivity has been found to be greater than that of basal ACTH or ODST. Two independent studies indicate that, when applying a reference interval cutoff of 29 pg/mL, basal ACTH concentrations ≤19 pg/mL (“clear negative”) and ≥39 pg/mL (“clear positive”) usually concur with TRH stimulation results whereas values between 20 and 40 pg/mL (“borderline” results perhaps representing a heterogeneous

mix of normal horses and those with early/mild PPID) produce unpredictable results

using TRH stimulation testing (Durham 2012; Rendle et al. 2012).

Plasma ACTH concentration fails to decrease significantly after pergolide therapy

Persistently increased plasma ACTH despite pergolide treatment suggests ongoing pars

intermedia dysfunction and incomplete pharmacologic control. If further increases in pergolide dosage described above fail to improve the clinical and/or laboratory findings then consideration should be given to using a different drug such as bromocryptine or cyproheptadine. As the latter is from a different drug class to pergolide it can be administered alongside the pergolide therapy. Given evidence of some PPID cases that show drug responsiveness several years after starting treatment as described above, then withdrawal of treatment following apparent treatment failure may be inadvisable

and

persistence might prove to be successful eventually. It is tempting to speculate

that

timing of response may depend on pathology within the pars intermedia with more

established or progressed disease requiring prolonged pergolide exposure before response is seen.

Serum insulin concentration remains increased despite normalisation of ACTH or ODST

Several studies have indicated that most PPID cases treated with pergolide and/ or cyproheptadine demonstrate a decrease in basal ACTH concentration and post- dexamethasone cortisol (Peters et al. 1995; Schott et al. 2001, Donaldson et al. 2002, Perkins et al. 2002; Andrews et al 2011; Rohrbach et al. 2012). However, measuring serum insulin may have greater prognostic meaning (McGowan et al. 2004; Walsh et al. 2009) but this has not been subject to much examination following treatment of PPID. Where hyperinsulinaemia remains there may be ongoing risk of laminitis and further action is recommended. Andrews et al. (2011) described a significant decrease in mean basal insulin (and glucose) in 113 PPID cases following pergolide treatment from 70 to 43 mU/L although post-treatment values were still commonly above the reference interval. Unpublished data from Liphook Equine Hospital similarly indicated a decrease in median basal insulin from 48 to 18 mU/L (P<0.001) in 43 PPID cases within 4 to 8 weeks of starting pergolide. Interestingly response in insulin was unrelated to response in ACTH concentrations.

4 to 8 weeks of starting pergolide. Interestingly response in insulin was unrelated to response in

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Treatment and monitoring of horses with Pituitary Pars Intermedia Dysfunction

Careful dietary control is an important response to hyperinsulinaemia by restricting non- structural carbohydrate access (e.g. cereals, grass) which is likely to further increase insulin secretion. However PPID horses should not be severely calorie restricted (unless obese) due to risk of exacerbating their catabolic status. If the horse is underweight, relatively high energy, non-hyperinsulinaemic feeds should be considered such as non-molassed sugar beet pulp, rice bran, alfalfa and vegetable oil. Adequate protein intake should also be ensured and non-hyperinsulinaemic ration balancers used where necessary. Exercise may be another means of improving peripheral insulin sensitivity and decreasing plasma insulin concentrations where lameness from laminitis allows. Metformin has recently been shown to decrease glycaemic and insulinaemic responses to NSC ingestion in normal, insulin resistant and PPID horses (Rendle et al. 2013) and might also be considered alongside pergolide treatment in persistently hyperinsulinaemic cases. Safety and efficacy of metformin in diabetes mellitus cases has not been established to date (Durham et al. 2009).

Continued laminitis

Continued laminitis is frequently associated with failure to control the PPID and continued hyperinsulinaemia (Walsh et al. 2009). Rechecking basal ACTH concentration to see whether or not the pituitary gland remains dysfunctional despite treatment is recommended. Efforts should also be made to control serum insulin concentrations as discussed above. Additionally appropriate farriery and digital support plays an important role in improving comfort and perfusion in laminitis cases.

Inappetance

Poor appetite was described in 6/38 (16%) pergolide treated horses in one study (Pongratz et al. 2010) and in 40/122 (33%) in another (Andrews et al. 2011). Decreased appetite tends to occur within the first month after initiation of treatment or following dosage increases and is generally transient although can persist or recur. Initial gradual introduction of pergolide may decrease the incidence of inappetance in treated cases. Where inappetance is seen then the pergolide dose should be reduced or temporarily stopped, followed by a gradual increase again. It is also mandatory to consider alternative causes of inappetance and further clinical or clinicopathological investigations, especially dental and oral examination is important.

Marked weight loss

Mild muscle wastage often observed as loss of topline is not uncommon in PPID cases although more pronounced weight loss is deserving of further investigation. Andrews et al. (2011) reported weight loss in >50% of 122 treated PPID cases although this was only considered to be abnormal in 11/122 (9%). Further clinical or clinicopathological investigations are warranted in such cases, especially considering checking plasma and urine glucose for signs of marked hyperglycaemia and diabetes mellitus (Durham et al. 2009).

checking plasma and urine glucose for signs of marked hyperglycaemia and diabetes mellitus (Durham et al.

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rEfErENCES

1. Andrews, F.M., McFarlane, D., Stokes, A.M., Schott, H.C., Bimes, R., Marteniuk, J., Hunt, J., Toppin, S., Kolb, D. and White, G.W. (2011) Freedom of Information Summary. Prascend Tablets, Pergolide Mesylate, for the control of clinical signs associated with Pituitary Pars Intermedia Dysfunction (Equine Cushing's Disease) in horses. Original New Animal Drug Application, NADA 141-331.www.fda. gov/downloads/AnimalVeterinary/Products/ Approved AnimalDrugProducts/

FOIADrugSummaries/UCM280354.pdf

2. Beck, D.J. (1992) Effective long-term treatment of a suspected pituitary adenoma with bromocryptine mesylate in a pony. Equine Vet Educ; 4, 119-122.

3. Copas, V.E. and Durham, A.E. 2012 Circannual variation in plasma adrenocorticotropic hormone concentrations in the UK in normal horses and ponies, and those with pituitary pars intermedia dysfunction. Equine Vet J. 44, 440-3.

4. Donaldson, M.T., LaMonte, B.H., Morresey, P., Smith, G. and Beech, J. (2002) Treatment with Pergolide or Cyproheptadine of Pituitary Pars Intermedia Dysfunction (Equine Cushing's Disease). Journal of Veterinary Internal Medicine 16, 742-746.

5. Durham, A.E. (2012) Comparison of basal ACTH concentration with TRH stimulation test results. Abstract Equine Endocrinology Summit, Boston.

6. Durham, A.E., Hughes, K.J., Cottle, H.J., Rendle, D.I. and Boston, R.C. (2009) Type 2 diabetes mellitus with pancreatic beta cell dysfunction in 3 horses confirmed with minimal model analysis. Equine Vet J. 41, 924-9.

7. Durham, A.E. and Copas, V.E.N. (2012) The temporal response of plasma ACTH concentration in horses with pituitary pars intermedia dysfunction subject to treatment with pergolide mesylate. Abstract 1 st European Equine Endocrinology Symposium, Berlin.

8. Dybdal, N.O., Hargreaves, K.M., Madigan, J.E., Gribble, D.H., Kennedy, P.C., Stabenfeldt, G.H. (1994) Diagnostic testing for pituitary pars intermedia dysfunction in horses. J Am Vet Med Assoc. 204:627-32.

9. Heinrichs, M., Baumgärtner, W., Capen, C.C. (1990) Immunocytochemical demonstration of proopiomelanocortin-derived peptides in pituitary adenomas of the pars intermedia in horses. Vet Pathol. 27, 419-25.

10. McFarlane, D., Breshears, M.A, Cordero, M., Banse, H., Hill, K., Carmichael, R., Maxwell, L.K. (2012) Comparison of plasma ACTH concentration, plasma a-MSH concentration, and overnight dexamethasone suppression test for diagnosis of PPID. Abstract Equine Endocrinology Summit, Boston.

and overnight dexamethasone suppression test for diagnosis of PPID. Abstract Equine Endocrinology Summit, Boston. 76

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11. McGowan, C.M., Frost, R., Pfeiffer, D.U., Neiger, R. (2004) Serum insulin concentrations in horses with equine Cushing's syndrome: response to a cortisol inhibitor and prognostic value. Equine Vet J. 36, 295-8.

12. McGowan, T.W., Pinchbeck, G.P. and McGowan, C.M. (2013) Evaluation of basal plasma a-melanocyte-stimulating hormone and adrenocorticotrophic hormone concentrations for the diagnosis of pituitary pars intermedia dysfunction from a population of aged horses. Equine Vet J. 45,

13. Miller, M.A., Pardo, I.D., Jackson, L.P., Moore, G.E. and Sojka, J.E. (2008) Correlation of pituitary histomorphometry with adrenocorticotrophic hormone response to domperidone administration in the diagnosis of equine pituitary pars intermedia dysfunction. Vet Pathol. 45, 26-38.

14. Perkins, G.A., Lamb, S., Erb, H.N., Schanbacher, B., Nydam, D.V. and Divers, T.J. (2002) Plasma adrenocorticotropin (ACTH) concentrations and clinical response in horses treated for equine Cushing's disease with cyproheptadine or pergolide. Equine Vet J. 34, 679-85.

15. Peters, D.F., Erfle, J.B. and Slobojan, G.T. (1995) Low Dose Pergolide Mesylate Treatment for Equine Hypophyseal Adenomas (Cushing's Syndrome). Proceedings American Association of Equine Practitioners 41, 154-155

16. Pongratz, M.C., Graubner, C. and Eser, M.W. (2010) Equine Cushing’s Syndrome. The effects of long-term therapy with pergolide. Pferdeheilkunde 26, 598-603.

17. Rendle D.I., Litchfield, E., Heller, J. and Hughes, K. (2012) Investigation of rhythms of secretion and repeatability of plasma adrenocorticotropic hormone concentrations in healthy horses and horses with pituitary pars intermedia dysfunction. Equine Vet J (in press)

18. Rendle, D.I., Rutledge, F., Hughes, K.J., Heller, J. and Durham, A.E. (2013) Effects of metformin hydrochloride on blood glucose and insulin responses to oral dextrose in horses. Equine Vet J (in press)

19. Rohrbach, B.W., Stafford, J.R., Clermont, R.S.W., Reed, S.M., Schott II, H.C., and Andrews, F.M. (2012) Diagnostic frequency, response to therapy, and long-term prognosis among horses and ponies with pituitary par intermedia dysfunction, 1993 –2004. J Vet Intern Med 26, 1027–1034

20. Schott, H.C., Coursen, C.L., Eberhart, S.W., Nachreiner, R.J., RefsalK.R., Ewart, S.L. and Marteniuk, J.V. (2001) The Michigan Cushing's Project. Proceedings American Association of Equine Practitioners 47, 22-24.

21. van der Kolk, J.H., Heinrichs, M., van Amerongen, J.D., Stooker, R.C., in de Wal, L.J., van den Ingh, T.S. (2004) Evaluation of pituitary gland anatomy and histopathologic findings in clinically normal horses and horses and ponies with pituitary pars intermedia adenoma. Am J Vet Res. 65, 1701-7.

in clinically normal horses and horses and ponies with pituitary pars intermedia adenoma. Am J Vet

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22. van der Kolk, J.H. Wensing, T., Kalsbeek, H.C. and Breukink, H.J. (1995) Laboratory diagnosis of equine pituitary pars intermedia adenoma. Domest. Anim. Endocrinol. 12, 35-39.

23. Walsh, D.M., McGowan, C.M., McGowan, T., Lamb, S.V., Schanbacher, B.J. and Place, N.J. (2009) Correlation of Plasma Insulin Concentration with Laminitis Score in a Field Study of Equine Cushing's Disease and Equine Metabolic Syndrome. J Equine Vet Sci 29, 87-94.

Score in a Field Study of Equine Cushing's Disease and Equine Metabolic Syndrome. J Equine Vet

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PhArMACOLOgIC trEAtMENt Of thE EqUINE MEtABOLIC SyNDrOME

Andy Durham BSc.BVSc.CertEP.DEIM.DipECEIM.MRCVS,

The Liphook Equine Hospital, Forest Mere, Liphook, Hampshire, GU30 7JG, UK. andy@TheLEH.co.uk Tel 0044 1428 723594 Fax 0044 1428 722263

EMS describes the clustering of several risk factors for laminitis (Frank et al 2010) which, if not subsequently controlled, predicts recurrence of laminitis. When laminitis cases are encountered it is essential that they are examined for the presence of such risk factors so that further control measures can be implemented. Potential recognised targets for managemental and therapeutic interventions include dietary quality and quantity, obesity, aerobic fitness, insulin resistance (IR) and hyperinsulinaemia. Although anecdotal observations and experiences indicate that laminitis risk is frequently reduced following effective control of these factors, currently there is no scientific proof of such. Obesity and consequent IR, are highly prevalent and fundamental risk factors in EMS cases and weight reduction is essential to achieve. In this author’s view, one of the major advances in EMS management in practice is the growing confidence and ability of practitioners to offer specific dietary advice to owners of obese horses following evidence-based recommendations (Geor and Harris 2009; Dugdale et al 2010). However, pharmacologic treatment of EMS might also be considered but should never be regarded as a substitute for managemental countermeasures. There is a danger that, given the practical difficulties of achieving weight loss in extremely metabolically efficient individuals, that some owners might regard pharmacologic assistance as an easier alternative to dietary and exercise control. This suggestion should be firmly repudiated in preliminary discussions of the proposed EMS- management plan as sole reliance on pharmaceutical interventions is highly likely to fail.

Pharmacologic management of the metabolic syndrome in humans is common and dependent on many different drug classes and actions. Although of interest to the equine practitioner, products found to be useful in human patients may frequently not apply to EMS cases due to inherent species differences in pharmacodynamics and pharmacokinetics in addition to further important physiologic and pathophysiologic differences relating to nutrition, nutrient metabolism, EMS and the metabolic syndrome. Thus far the only pharmacologic agents have received significant attention in EMS cases comprise L-thyroxine, metformin hydrochloride and pioglitazone.

agents have received significant attention in EMS cases comprise L-thyroxine, metformin hydrochloride and pioglitazone. 79

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L-thyrOXINE (LEVOthyrOXINE)

Early mistaken suspicions that obese, lethargic, laminitis-prone individuals were clinically hypothyroid, first led to the use of L-thyroxine (e.g. Thyro L, Lloyd Inc, Shenandoah, Iowa; Soloxine, Virbac Ltd, Bury St Edmunds, Suffolk) for the intention of replacement therapy in such cases. Although it is now accepted that hypothyroidism is an extremely rare occurrence in horses that does not play a role in laminitis-susceptibility, evidence suggests that exogenous thyroid hormone may nevertheless have beneficial effects in obese laminitis-prone subjects. One study found that mares typically lost approximately 0.5% bodyweight weekly when treated with L-thyroxine on an increasing dosage regime from 0.05-0.20 mg/kg daily over 8 weeks (Sommardahl et al 2005). In a further more prolonged study by the same group, daily administration of 0.10 mg/kg L-thyroxine was associated with approximately 0.6% bodyweight loss per week over the course of

16

weeks although weight loss did not continue with longer term treatment for up to

48

weeks (Frank et al 2008b). It was suggested that L-thyroxine leads to lipolysis and

mobilisation of adipose stores due to an increased basal metabolic rate (Frank et al 2008b). In association with the weight loss, serum insulin concentrations were seen to decrease slightly and insulin sensitivity approximately doubled during treatment (Frank et al 2008b). Significant adverse health effects of exogenous L-thyroxine were not seen although minor cardiac changes are described (Frank et al 2008a). Use of L-thyroxine in EMS cases is recommended alongside dietary restriction, both to augment the effect on weight loss and also to guard against the possible adverse effects of increased appetite during treatment (Frank 2011). Typically a dose of approximately 0.1 mg/kg orally q 24 hours is recommended for between 3 and 6 months depending on response in body condition. At the end of the treatment period the drug should be gradually withdrawn over 2-4 weeks to allow reestablishment of normal responsiveness of the pituitary-thyroid axis. Outside of the USA, use of L-thyroxine is greatly limited by cost.

MEtfOrMIN hyDrOChLOrIDE

Use and effects in other species

Metformin, an inexpensive biguanide drug, has become the mainstay of medical therapy for human patients with the metabolic syndrome over the last 50 years (Nathan et al 2009). For such a widely prescribed product, its mode of action is poorly understood although it is one of few pharmaceutical agents shown to decrease cardiovascular disease, the major morbidity and cause of mortality in humans with the metabolic syndrome (UKPDS 1998). Metformin promotes phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), an important regulator of energy metabolism. Biguanide drugs have anti- hyperglycaemic effects, with the most widely quoted action of metformin being as an anti-hyperglycaemic insulin-sensitizer leading to inhibition of hepatic gluconeogenesis and stimulation of glucose uptake in muscle and adipose tissue (Stumvoll et al 1995; Bailey 2005; Hays et al 2008). However, several other pharmacologic effects of

and adipose tissue (Stumvoll et al 1995; Bailey 2005; Hays et al 2008). However, several other

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Pharmacologic treatment of the Equine Metabolic Syndrome

metformin are recognised and the relative importance of the insulin-sensitizing effect of biguanides was initially brought into question many years ago (Caspary and Creutzfeldt 1973). Furthermore it is evident that metformin exhibits unusual pharmacokinetic and pharmacodynamic properties worthy of consideration.

There is a lack of correlation between systemic plasma drug concentrations and glycaemic control in humans treated with metformin (Marchetti et al 1987). This is probably explained by the particular affinity that metformin and other biguanides have for enterocytes. In both mice and humans biguanides have been shown to accumulate in the gastrointestinal mucosa, (especially jejunum and ileum) at around 100 times the concentrations found in plasma and other tissues following oral administration (Wick et al 1960; Yoh 1967; Wilcock and Bailey 1994; Bailey et al 2008). Plasma membrane monoamine transporter (PMAT), identified on the apical membrane of human enterocytes, has been shown to have a high affinity for metformin and is responsible for intestinal uptake of drug (Zhou et al 2007). Small intestinal metformin accumulation also occurs following intravenous administration, albeit with lower tissue concentrations compared with oral dosing (Wilcock and Bailey 1994). This deep enterocytic compartment of drug accumulation is also clearly functionally important as rodent studies have demonstrated a more profound and prolonged anti-hyperglycaemic effect of metformin when administered into the duodenum compared with the intravenous route (Stepensky et al 2002), leading to the description of an important “first-pass pharmacodynamic effect” of metformin prior to any systemic pool of drug being established. Thus metformin efficacy is more directly related to pre-systemic drug concentration within enterocytes rather than systemic plasma drug concentrations

Consistent with enteric accumulation, several studies have shown that metformin and other biguanides have marked effects on intestinal glucose uptake, utilisation and systemic absorption. Numerous in vivo studies have demonstrated a decreased glycaemic response to oral glucose dosing when humans, dogs, guinea pigs, hamsters or rats are pre-treated with metformin and other biguanides (Czyzyk et al 1968; Love 1969; Hollobaugh et al 1970; Lorch 1971; Caspary and Creutzfeldt 1973; Bailey et al 1992; Sakar et al 2010). However, this is not a result of glucose malabsorption but rather increased glucose uptake and utilisation by enterocytes in the presence of metformin (Mithieux et al 2006; Bailey et al 2008; Sakar et al 2010). Enterocytes normally show high levels of glucose utilisation via glycolytic pathways (Krebs 1972), which is further augmented in the presence of metformin in both fed and fasted states (Wilcock and Bailey 1990). Thus absorbed glucose is primarily metabolised inefficiently by enterocytes into lactate rather than being assimilated into the systemic circulation (Berger and Kunzli 1970; Caspary and Creutzfeldt 1973; Penicaud et al 1989; Wilcock and Bailey 1990; Bailey et al 1992).

Consistent with the effects of metformin described above, there is a detectable post- prandial hyperlactaemia noted during metformin therapy but this is generally mild and not clinically concerning (Wilcock and Bailey 1990; Bailey et al 1992; Bailey et al 2008). Lactic

is generally mild and not clinically concerning (Wilcock and Bailey 1990; Bailey et al 1992; Bailey

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acidosis was recognised as an important adverse effect of phenformin, a predecessor of metformin (Bergman et al 1978), but this does not appear to be a significant concern with metformin use in humans with normal renal and hepatic function (Bailey and Turner 1996), although perhaps merits further investigation in horses. In humans, metformin is not protein bound and is excreted entirely via the kidneys unchanged into urine (Pentikainen et al 1979) and therefore use in patients with renal insufficiency is therefore not recommended.

Studies of intestinal glucose absorption have indicated the presence of both an active sodium glucose transporter-1 (SGLT-1) and a passive GLUT2 transporter that enable uptake of glucose from the intestinal lumen and are expressed in response to luminal sugars (Merediz et al 2004; Kellett et al 2008). Lenzen et al (1996) found that metformin treatment in rats was associated with increased SGLT-1 gene expression in the small intestine but had no effect on expression of GLUT2 genes. In contrast, Sakar et al (2010) found that metformin decreased SGLT-1 and increased GLUT2 abundance in rat jejunum, an effect that was dependent on metformin phosphorylating AMP-K. Thus the precise interaction between metformin and glucose transporters has yet to be clarified.

Use and effects in equids

A study of laminitis-prone horses and ponies reported a significant decrease in plasma

glucose and insulin within 2 weeks of beginning metformin therapy at 15 mg/kg q 12 hours (Durham et al 2008). However, subsequent studies indicated very poor oral

bioavailability of metformin in horses of only 7% following fasting and 4% in the fed state (Hustace et al 2009), compared with 50-60% in humans and rats (Pentikainen et al 1979; Wilcock and Bailey 1994; Stepensky et al 2002). Further studies found no detectable effect of metformin on peripheral insulin sensitivity in both normal horses (Firschmann et

al 2009) and insulin resistant ponies (Tinworth et al 2012) at 15 mg/kg, casting serious

doubt on the existence of any real clinical benefits of the drug in EMS cases.

However, all of the findings in the above equine studies may be reconciled by hypothesising that metformin in horses may have negligible systemic effects due to poor bioavailability, but may well maintain significant direct enteric effects as described in other species above. In the original study of the use of metformin in laminitis-prone horses and ponies, an acute mild hypoglycaemic effect was noted following metformin with an approximate 10% decrease in plasma glucose 3 hours following drug administration (Durham et al 2008). A further study has recently confirmed significant moderation of hyperglycaemia and hyperinsulinaemia in horses when metformin was administered at a dose of 30 mg/ kg prior to oral glucose dosing (Rendle et al 2013) also consistent with the findings in other species. This effect was found in normal horses, horses with dexamethasone- induced insulin resistance, and in horses with naturally occurring insulin resistance. Thus there is accumulating evidence that metformin decreases enteric glucose absorption and subsequent insulinaemia in horses as well as other species.

that metformin decreases enteric glucose absorption and subsequent insulinaemia in horses as well as other species.

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Pharmacologic treatment of the Equine Metabolic Syndrome

It is relevant that current suspicions of the apparent pathogenetic links between insulin resistance and laminitis focus on diet-induced hyperinsulinaemia rather than tissue insulin insensitivity per se (Asplin et al 2007; de Laat et al 2010,2012). In this respect, the lack of any detectable insulin sensitising effect of metformin in horses (Firschmann et al 2009; Tinworth et al 2012), yet the demonstration of moderation of hyperglycaemia and hyperinsulinaemia (Durham et al 2008; Rendle et al 2013) serves to maintain clinical interest in the drug. However, if the effect of metformin is to decrease post-prandial hyperglycaemia and hyperinsulinaemia then its use in subjects where diet is controlled as per recommendations (i.e. low NSC and mildly glycaemic/insulinaemic) is questionable. The drug might be best applied in insulin resistant cases that are still ingesting significant NSC from grazing, for example PPID cases or EMS cases that are being allowed some limited grazing following on from an effective weight loss and exercise control programme. The moderation of glucose absorption might also be expected to assist weight control in such individuals. Rather than straightforward twice-daily dosing, it might be wise to target drug administration pre-turnout to limit the subsequent glycaemic and insulinaemic effect of grazing. It should also be stated however, that any putative clinical benefits of metformin in horses are still based largely in anecdote although one study commented that laminitis was improved in 14/18 (78%) treated subjects (Durham et al 2008). Further studies are clearly required.

Despite frequent gastrointestinal symptoms in human patients treated with metformin, no adverse effects of oral therapy have been reported in horses using doses up to 30 mg/kg (Durham et al 2008, Firshmann et al 2009, Hustace et al 2009, Tinworth et al 2012, Rendle et al 2013). Given the relative unimportance of achieving high plasma drug concentrations, along with the commonly encountered practical problem of poor palatability in horses, further investigation of lower doses of metformin in horses might be warranted.

thIAzOLODINEDIONES

Thiazolidinediones (TZDs) are commonly prescribed insulin-sensitising drugs used in metabolic syndrome patients (Bailey 2005) and recent investigation in horses have revealed a reasonable pharmacokinetic profile (Wearn et al 2011) some potential clinical benefits of pioglitazone. One study (Suagee et al 2011) administered pioglitazone at a dose of 1 mg/kg daily to lean, healthy horses and found that although insulin sensitivity was not changed significantly by the treatment either before or after lipopolysaccharide (LPS)-induced IR, pioglitazone was associated with increased abundance of GLUT1 and CD36 protein and insulin receptor transcripts in skeletal muscle. Additionally, apparent protection against endotoxin-induced suppression of GLUT4 was seen in adipose tissue. No effects of pioglitazone on LPS-induced inflammatory markers was detected in a further study (Wearn et al 2012).

No effects of pioglitazone on LPS-induced inflammatory markers was detected in a further study (Wearn et

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2. Bailey CJ. 2005 Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diabetes Obes Metab. 7: 675-91

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whAt IS LAMINItIS fOr A PODIAtrISt?

D’Arpe L.

dVM, Phd E-mail address: lorenzodarpe@tiscali.it

kEywOrDS

Laminitis, Equine foot, Sole Depth

ABStrACt

Authors want to put in light what is Laminitis for a podiatrist; is this term a valid term to describe the pathology? We should better distinguish between laminar and /or solear

coriumitis?

Author wants to introduce the reader to Laminitis in a podiatrist perspective

A great number of studies has been focused on Laminitis during last decades to have

a deeper knowledge about the complexity of pathogenic mechanism and have valuable

therapeutic instruments.

Today there exist two main Hypothesis about Laminitis Pathogenic Mechanism.

1°Vascular Theory:

The ischemia and conseguent reperfusion are the innings events following the direct or indirect stimulation of vasoactive substances as endotoxine and vasoactive amines.

2° Enzymatic Theory :

The Metalloproteinasi activated by LAMINITIS TRIGGERS FACTORS are responsible of the dermo- epidermic separation.

: The Metalloproteinasi activated by LAMINITIS TRIGGERS FACTORS are responsible of the dermo- epidermic separation. 87

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The evidency of digital poulse changements and the foot temperature are the elementary signs of the circulation importance as a determinant factor involved in Laminitis process.

The heat presence in the feet with digital pulse are signs of the vascular activity, many

authors (Goley, Garner et Allen

have observed that ischemia or ematic flux reduction

)

in

feet are present in Laminitis cases.

A

better knowledge of Pathology will allow to standardize Therapies more effectives and

in

the future the prevention.

The horse finger is enclosed by the wall and sole, so is exposed to secondary compression of inflammatory oedema of a structure enclosed into the hoofcapsule.These anatomical soft and hard structures can induce the inflammation cascade with a mechanism similar to cerebral oedema.

The H-L zone contains the digital laminar dorsal vessels in a space of only 3 mm. (Amy Rucker)

dorsal vessels in a space of only 3 mm. (Amy Rucker) courtesy of Amy Rucker Robinson

courtesy of Amy Rucker

Robinson has observed that there i not much room for the dilatation of vassels and interstitial oedema between two relative rigid structure (the hoof wall and PIII), so the increasing interstitial pressure is a conseguence collapse of the thin room where the digital lamellar vassels are leaning.

The artero-venous anastomosis could have ,according to Molyneux, a function of safety valves that opens to protect capillars from an eccessive pressure caused by an obstruction of venules.

Using the hoofwall temperature as an index of the digital ematic flux, Hood concluded that digital perfusion in Laminitis acute cases can vary secondary to the gravity of the pathology, if the vascular architecture is manteined; othrwise the vascular architecture is partially or totally destroyed.

if the vascular architecture is manteined; othrwise the vascular architecture is partially or totally destroyed. 88

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What Is Laminitis For A Podiatrist?

The ematic flux reduction is the result of an insufficient intraluminal pressure and/or vasocostrinction or dilatation of the dermal circulation. This is particularly important in a microcirculation unable to autoregulate (Robinson).

Microvascular trombi and oedema are evident in the first 24H and the primary dermal laminae aemorragia in the first 72H (Hood et al.).

Laminitis in author’s opinion and experience is a secondary dermatitis similar to human diabet, wich unfortunately does not respond to temporary antidotes as insuline but fortunately respond to automassage and prolonged cryotherapy.

The PIII vertical dislocation and rotation are the conseguence of the laminar tissue istopathologic lesion, wich is no more able to mecanically substain the PIII-hoofcapsule bond; this phenomenum causes the partial or total compression of the coronary plexus and the vessels enclosed between two relative rigid structures with the compromission of the dig- ital perfusion. (L.d’arpe).

Here following the author report of a report experience to set a standard of the Soledepth as a standard of foot health index.

MANUSCrIPt

AuthoRS: Lorenzo D’Arpe*, Daniele Bernardini*.

* department of clinical sciences, University of Padova (Italia)

INtrODUCtION

This is a retrospective study of 54 podal pathology cases with a loss of performance caused by inflammation of the dermal fimbriae of the sole.

Lameness is the more frequently clinical sign horse and the horse foot is the more frequently anatomic region involved and exposed to direct physical exam by X-ray examinations (M. Kummer 2004).

It was executed a retrospective study on 54 horses in the period 2005-2007, 28 Anglo- Arabs (12 geldings, 13 females and 3 stallions), 25 thoroughbreds (14 geldings, 10

in the period 2005-2007, 28 Anglo- Arabs (12 geldings, 13 females and 3 stallions), 25 thoroughbreds

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females and 2 stallions), 1 Lusitanian (Female affected by EMS), aged between 3 and 15 years and bodyweight between 250 and 600 Kg. All examined horses showed signs of a mild bilateral front limb lameness, 0° or I° of orthopedic scale (O’Connor, 1952 (1990)) and 0° of the Obel scale (1948), all horses were referred for a loss of the performance.

Clinical exam of the foot pointed out presence of rings around the hoof wall in 20 horses, a symmetric pulse and mild heat of the coronary bend in all horses; pain of the sole was relieved by finger pression in 15 horses, by hoof tester in all horses. The digit flexion test was positive only in 16 cases.

X-ray exams highlighted bone remodeling of the coffin bone (PIII) in correspondence to the sole pain area (60% apex of the frog (apex of PIII), 15% middle and 25 % caudal part of the frog (Solar aspect of PIII and palmar processuses)).

Thank to X-rays podiatry view images and in 14 cases venograms we have diagnosed an inflammation of the solar corium of the foot and set a therapeutic protocol using massaging shoeing (Self Adjusting Palmar Angle), cushion support and box rest with deep bedding.

MAtErIAL AND MEthODS

13 horses underwent clinical exams in the Department Of Veterinary Clinical Sciences,

University Of Padua and 41 horses have been visited in farms and stables in Sardinia Island.

All the front feet of the examined horses have been carefully unshod and thoroughly cleaned, the X-ray images were taken, with the horse standing in 4 feet posture, in 0° Latero-Medial projection with the x-ray beam oriented perpendicular to the cassette and pointed at the middle of the solar aspect of PIII, to reduce the distortion effect, at a distance of 80 cm to reduce and measure the magnification effect (D’Arpe L. et al 2006).

X-rays examinations have been executed with a portable PX-20HF unit and the digital CR 2430 V/CR 35 V [a] development system with Fuji STV standard cassettes.

In order to raise the foot and orient correctly the X-ray beam at the solar aspect of PIII were used 2 wooden Podoblocks 9 cm height (Lateral and D.P. Positioning Blocks [b]).

14 horses underwent Venography examination following the technique we described in

previous studies (D'Arpe et al. 2008).

underwent Venography examination following the technique we described in previous studies (D'Arpe et al. 2008). 90

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rESULtS

X-ray exams showed no vertical dislocation and rotation, except one horse that had a bilateral 10° rotation without vertical dislocation. All horses did show a Sole depth below 15 mm.

In 46 horses was revealed the presence of a radiotrasparent line or area under the

solar aspect of PIII, in 20 of them was found in correspondence a small fistula with leakage of liquid, yellow, transparent and odorless material, referred to be serum. In the cases where the fistula was present, the lameness was less important; in the

34 cases where the fistula was not present yet and seroma was detected by X-ray

images under the solar aspect of PIII or venograms images in the circumflex vessels area, the lameness was more important and the foot pain response to finger pression or hoof-tester was considerably accentuated and the digital pulse more important. The Seroma location was detected clinically previously with palpation exam with finger pression or hoof-tester and confirmed by x-rays images that helped in finding the best way to fistolize the serum that was found in 60% of the studied feet at apex of the frog in correspondence of the apex of PIII, in 15% in the middle of the frog in correspondence of the solar aspect of PIII and in 25 % in the caudal part of the frog in correspondence of palmar processuses.

In the horses that have shown a chronic recidive and repetitive synthomatology above years was also observed a bone remodeling of PIII with a more or less important bone loss of the solar aspect.

The bone density has been measured with a special software tool available in the digital X-ray system that tracking a line parallel to the solar aspect of PIII gives a relative measure of the bone density of PIII.

Venography examinations performed showed the normal anatomy and functionality of the coronary plexus, dorsal laminar vessels and bulbar vessels, but the circumflex vessels have always been compressed and the solar Papillae or Fimbriae of the podovillus cheratogenus of the sole never visible.

15 horses followed a complete therapeutic protocol (massaging also in static shoeing

(SAPA), sole arch support and box rest with deep bedding) and after a shoeing period of time of 60 days the real sole doubled and these went back progressively to previous activity with same or better results.

18 horses followed partially the protocol and went back to previous activity, but did show

recidive after 1-4 weeks.

21 horses did not follow a therapeutic protocol and continued to show the lameness

and even if treated with FANS when the pharmaceutical effect was ended continued to recidive.

to show the lameness and even if treated with FANS when the pharmaceutical effect was ended

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DISCUSSION AND CONCLUSIONS

The comments of a previous study D'Arpe et al. (2008) report on the biomechanics of the foot pump vascular mechanism and lead us to conclude that the prolonged lack of blood flow of a vascular district can affects long-term bone remodeling and furthermore in this study we have highlighted the localized vascular damage of the circumflex vessels that can lead to a bone remodeling of the solar aspect of PIII. The bone line density is a software development of the digital system, which makes a relative, not absolute, little scientific weight, but, in our opinion, high usefulness in practice and that definitely needs more scientific proof, but we could not, however, now, neglect the observation of the correspondence between the data obtained on the bone density loss and the clinic observation. We have noticed, according also to Redden (2007) that the horses with a sole depth thicker than 15 mm can be asymptomatic and less exposed to the risk of showing lameness and to develop a catastrophic and well known Laminitis. So we agree with Redden (2003), that the horses with the sole depth of less than 15 mm and a negative Palmar Angle (PA) are more predisposed to a pathological condition of the foot.

We also agree with the comments of Nicholas Frank (2007) on “Equine Metabolic Syndrome”, who describes “a pro inflammatory state of Laminitis, which along to the negative effect on vascular tone and consequent vasoconstriction that occurs in cases of insulin resistance and endothelial dysfunction, leads to the release of vasoactive substances from the intestinal tract and prepare those horses affected by equine metabolic syndrome episodes of Laminitis”. We conclude therefore that factors such as insulin resistance or repeated concussion on a fragile and thin sole (<15 mm) may compromise the vascular integrity of the circumflex vessels and Papillae of the sole with consequent low oxygenation and damage the matrix of the sole. Further more we noticed that the horse affected by EMS followed the complete therapeutic protocol and after doubling the sole with an average of more than 15 mm was completely sound and did not show the episodes of Laminitis after that treatment.

We conclude that in all the horses observed in this study the poor protection of the vascular bed due to a sole too thin to absorb correctly the great biomechanics insults of repeated concussion, have achieved a poor oxygenation, activation of MMP3, and consequent damage of the corium cheratogenus of the sole, leading to a solar corionitis with overproduction of serum collected in a seroma, bone remodeling of the solar aspect of PIII. Finally we consider this typical and frequent lameness as a developmental phase of a so called “Laminitis” that after this study we would rather prefer call “Solar Corionitis”, because in our opinion the anatomical term to define the pathology of this retrospective lameness study should be “Solar Corionitis” and as a consequence “Laminitis” term, in our opinion, is not more anatomically exhaustive in describing this developmental phase, but following what we have highlighted in this retrospective study we should better distinguish between Solar and Laminar Corionitis.

what we have highlighted in this retrospective study we should better distinguish between Solar and Laminar

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BIBLIOgrAPhy

1. D’Arpe L., Coppola L.M., Guidi V., Bernardini D. “Evaluation of the magnification effect related to the focus film distance and the distortion effect related to the highness of foot positioning blocks in the normal radiology of the equine foot”, proceedings AVEF 2006, Versailles, France.

2. D’Arpe L., Coppola L.M., Bernardini D. “How to do a Digital Venography in a standing horse”, proceedings of the WEVA congress, Moscow (Russia) 2008

3. D’Arpe L., X.Moreau, L.M.Coppola, D.Bernardini, S.Masiero “Equine Digital Venogram in Relation to the Biomechanics of the Foot” proceedings of the SIVE congress, European congress of the year, Venice (Italy) 2008

4. Nicholas Frank “Equine Metabolic Syndrome: aren’t they just fat?”